Dr. Michael Mullan Article Published in Herald Tribune: Dr. Michael Mullan: Volunteer to help fight Alzheimer’s

Michael Mullan Alzheimer's Researcher

Dr. Michael Mullan CEO of Roskamp Institute

More than 20 years ago, scientists at The Roskamp Institute were among those to first discover the first known genetic cause of Alzheimer’s disease. The discovery had major consequences: The genetic errors were discovered in the amyloid gene. This discovery focused attention on amyloid and it is now recognized as a critical component of all Alzheimer’s disease, not in just the very rare early-onset cases (with the disease starting between the ages of 50 and 60).

As a result of this focus, it is now widely accepted that amyloid (a small protein) accumulation is an early contributor to the sequence of events that lead to brain degeneration and cognitive decline.

The discovery allowed the generation of so-called “transgenic” mice, which carry the human genetic errors that cause early-onset Alzheimer’s disease. These mice are born normally, and are cognitively normal until they grow older; at which point they begin to lose the ability to remember new information, just as Alzheimer’s patients do.RI Button 1

You can read more about this: http://www.heraldtribune.com/article/20130605/columnist/306059999

Donation Campaign – 36 hour giving challenge campaign

 

Most of the Roskamp Institute’s funding comes from grant funding and the general public — people like you. Your gift makes a difference in the lives of people facing diseases such as Alzheimer’s Disease, Head Trauma, Drug Addiction, Cancer and Tourette’s Syndrome. Your contribution to the not-for-profit (501[c]3) Roskamp Institute is tax deductible and supports research to improve treatment and to ultimately develop a cure for these devastating diseases.

If you contribute to the Roskamp Institute by participating in the 36-Hour Giving Challenge at Giving Partner Challenge anytime between March 27 at 6 am and March 28 at 6 pm, your donation stands a great chance of being matched penny for penny.

Help us get a special grant for attracting the most donors. (We can win up to $20,000 by having the most unique donors give $25 or more to us.) Help us earn one of 20 grants for being among the first nonprofits to have 50 donors donate $50 or more.One random donor per hour will receive an additional $250 added to his/her donation. That could be you!You can help us get one of two $5,000 grants by visiting our profile on www.thegivingpartner.org during the challenge.

The Roskamp Foundation, a private foundation established by Bob and Diane Roskamp to administer all their philanthropic work in Sarasota and throughout the country. The Foundation has pledged to match all gifts to the Institute dollar for dollar that come in during the 36-Hour Giving Challenge, up to a maximum total of $50,000.

The money raised through the Giving Challenge will be used to further our research and will make a significant difference in the lives of people facing diseases such as Alzheimer’s Disease, head trauma, Gulf War Syndrome, Autism, drug addiction and Tourette’s Syndrome.

All donations must be made online. When you are ready to make your donation on March 27, go to www.GivingPartnerChallege.org, enter Roskamp in the box at the upper right where it says “Search for Organizations” and then click Search. You will then go to a page with the Institute’s information which you will click on and the donation form will appear.

However, you can make your pledge right now and you won’t have to get up at 6:00 a.m. Just click below:

http://www.rfdn.org/donate36hrs.html

to DONATE NOW! and we’ll process your donation for you between March 27, 6 a.m. and March 28, 6 p.m.

Thank you for your gift to the Roskamp Institute to help us continue our very important work. If you have any questions or if you would like to make your donation right now over the phone, please call me directly at 941-752-2949 extension 390.

To learn more about supporting Roskamp Institute, please contact:

Mr. Steve Klindt
Director of Development
Roskamp Institute

2040 Whitfield Avenue,
Sarasota, FL 34243

Phone: 941-752-2949 ext 390
Fax: 941-752-2948

Email: Steve Klindt

Anti-Tumoral Activity of a Short Decapeptide Fragment of the Alzheimer’s Abeta Peptide.

The inhibition of angiogenesis is regarded as a promising avenue for cancer treatment. Although some antiangiogenic compounds are in the process of development and testing, these often prove ineffective in vivo, therefore the search for new inhibitors is critical. We have recently identified a ten amino acid fragment of the Alzheimer Abeta peptide that is anti-angiogenic both in vitro and in vivo. In the present study, we investigated the antitumoral potential of this decapeptide using human MCF-7 breast carcinoma xenografts nude mice. We observed that this decapeptide was able to suppress MCF-7 tumor growth more potently than the antiestrogen tamoxifen. Inhibition of tumor vascularization as determined by PECAM-1 immunostaining and decreased tumor cell proliferation as determined by Ki67 immunostaining were observed following treatment with the Abeta fragment. In vitro, this peptide had no direct impact on MCF-7 tumor cell proliferation and survival suggesting that the inhibition of tumor growth and tumor cell proliferation observed in vivo is related to the antiangiogenic activity of the peptide. Taken together these data suggest that this short Abeta derivative peptide may constitute a new antitumoral agent.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer’s disease.

Alzheimer’s disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of beta-amyloid (Abeta) peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Abeta peptides which have been shown to be antiangiogenic. To determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Abeta peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates. In addition, we show that Abeta inhibits the angiogenesis stimulated by glioma cells when cocultured with human brain microvascular cells on a Matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Characterization and use of human brain microvascular endothelial cells to examine β-amyloid exchange in the blood-brain barrier. Bachmeier C, Mullan M, Paris D.

Alzheimer’s disease (AD) is characterized by excessive cerebrovascular deposition of the β-amyloid peptide (Aβ). The investigation of Aβ transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Aβ exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism of key Aβ transport proteins significantly altered the bi-directional transcytosis of fluorescein-Aβ (1-42) across the HBMEC model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid fluorometric method of assessing Aβ exchange between the periphery and the brain.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Depletion of CXCR2 inhibits γ-secretase activity and amyloid-β production in a murine model of Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline. Recent studies from our group and others have suggested that certain G-protein coupled receptors (GPCRs) can influence the processing of the amyloid precursor protein (APP). Earlier, we demonstrated that stimulation of a chemokine receptor, CXCR2, results in enhanced γ-secretase activity and in increased amyloid-beta (Aβ) production. Taken together, results obtained from in vitro studies indicate that therapeutic targeting of CXCR2 might aid in lowering Aβ levels in the AD brain. To better understand the precise function and to predict the consequences of CXCR2 depletion in the AD brain, we have crossed CXCR2 knockout mice with mice expressing presenilin (PS1 M146L) and APPsw mutations (PSAPP). Our present study confirms that CXCR2 depletion results in reduction of Aβ with concurrent increases of γ-secretase substrates. At the mechanistic level, the effect of CXCR2 on γ-secretase was not found to occur via their direct interaction. Furthermore, we provide evidence that Aβ promotes endocytosis of CXCR2 via increasing levels of CXCR2 ligands. In conclusion, our current study confirms the regulatory role of CXCR2 in APP processing, and poses it as a potential target for developing novel therapeutics for intervention in AD.

For more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier.

Several large population-based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro, whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showing that the Aβ-lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice, and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity, but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine.

Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp). The present study expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P-gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood-brain barrier (BBB). The HBMEC were treated for 1 h with various concentrations (500 nM to 50 µM) of venlafaxine and desvenlafaxine. Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P-gp (2-fold) and BCRP (1.75-fold) in a dose-dependent manner, while treatment with desvenlafaxine had no effect on drug efflux transporter expression. To determine the functional significance of this effect, the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption, were examined. Treatment with venlafaxine (1-50 µM) for 1 h significantly reduced the apical-to-basolateral permeability of R123 across the BBB model (30%) and Caco-2 cell monolayers (25%), indicative of increased drug efflux transporter expression at the apical membrane. Conversely, desvenlafaxine had no effect on R123 permeability in either cellular model. These studies indicate that venlafaxine, but not desvenlafaxine is an inducer of drug efflux transporter expression, which consequently increases the potential for clinical drug-drug interactions. Therefore, based on these preliminary results, caution should be taken when prescribing venlafaxine with other P-gp substrates.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier.

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer’s disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer’s disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer’s disease and could open the door to a new class of therapies for the treatment of this disease.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum β-Amyloid.

We examined the usefulness of brief neuropsychological tests and serum Aβ as a predictive test for detecting MCI/AD in older adults. Serum Aβ levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw. Twenty-eight of the subjects subsequently developed MCI (n = 18) or AD (n = 10) over the follow-up period. Baseline measures of global cognition, memory, language fluency, and serum Aβ(1-42) and the ratio of serum Aβ(1-42)/Aβ(1-40) were significant predictors for future MCI/AD using Cox regression with demographic variables, APOE ε4, vascular risk factors, and specific medication as covariates. An optimal sensitivity of 85.2% and specificity of 86.5% for predicting MCI/AD was achieved using ROC analyses. Brief neuropsychological tests and measurements of Aβ(1-42) obtained via blood warrants further study as a practical and cost effective method for wide-scale screening for identifying older adults who may be at-risk for pathological cognitive decline.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Flavonoids lower Alzheimer’s Aβ production via an NFκB dependent mechanism.

Alzheimer’s disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of Aβ peptides. Westernblots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and Aβ production. A cell free chemoluminescent assay using human recombinant BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The effect of flavonoids on NFκB activation was determined by using a stable NFκB luciferase reporter cell line. Molecular docking simulations were performed to predict the binding of flavonoids to the BACE-1 catalytic site. Real time quantitative PCR was used to determine the effect of flavonoids on BACE-1 transcription. We show in a cell free assay that flavonoids are only weak inhibitors of BACE-1 activity. Docking simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhibitors as they appear to adopt various docking poses in the active site pocket and have weak docking scores that differ as a function of the BACE-1 structures studied. Moreover, a weak correlation was observed between the effect of flavonoids on Aβ production in vitro and their ability to lower BACE-1 activity suggesting that the Aβ lowering properties of flavonoids in whole cells are not mediated via direct inhibition of BACE-1 activity. We found however a strong correlation between the inhibition of NFκB activation by flavonoids and their Aβ lowering properties suggesting that flavonoids inhibit Aβ production in whole cells via NFκB related mechanisms. As NFκB has been shown to regulate BACE-1 expression, we show that NFκB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit Aβ and sAPPβ production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Identification of Plasma Biomarkers of TBI Outcome Using Proteomic Approaches in an APOE Mouse Model.

Abstract The current lack of diagnostic and prognostic biomarkers for traumatic brain injury (TBI) confounds treatment and management of patients and is of increasing concern as the TBI population grows. We have generated plasma proteomic profiles from mice receiving TBI by controlled cortical impact at either 1.3 mm or 1.8 mm depth, comparing these against those of sham injured-animals to identify plasma biomarkers specific to mild or severe TBI at 24 hours, 1 month, or 3 months post-injury. To identify possible prognostic biomarkers, we used apolipoprotein E (APOE)3 and APOE4 transgenic mice, which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI. Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation – iTRAQ) we have identified proteins that are significantly modulated as a function of TBI and also in response to the TBI*APOE genotype interaction, the latter representing potential prognostic biomarkers. These preliminary data clearly demonstrate plasma protein changes that are not only injury dependent but also interaction dependent. Importantly, these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3-month time point, which is a considerable time post-injury in the mouse model, and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury. Furthermore, our identification of clusters of functionally related proteins indicates disturbance of particular biological modules, which potentially increases their value beyond that of solitary biomarkers.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Anatabine lowers Alzheimer’s Aβ production in vitro and in vivo

Brain Aβ accumulation represents a key pathological hallmark in Alzheimer’s disease. In this study, we investigated the impact of anatabine, a minor alkaloid present in plants of the Solanacea family on Aβ production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer’s disease. In vitro, anatabine lowers Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a dose dependent manner and reduces sAPPβ production without impacting sAPPα levels suggesting that anatabine lowers Aβ production by mainly impacting the β-cleavage of APP. Additionally, we show that anatabine lowers NFκB activation at doses that inhibit Aβ production in vitro. Since NFκB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Aβ production), we determined the impact of anatabine on BACE-1 transcription. We show that anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Aβ lowering properties of anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with anatabine for four days significantly lowers brain soluble Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a transgenic mouse model of Alzheimer’s disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Aβ accumulation.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer’s disease.

Expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer’s disease (AD). Moreover, we also found that, in an Alzheimer’s mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α (TNF-α) signaling. The role of TNF-α receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1-deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-α. In TNFR2-deleted cells, TNF-α promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-α treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity.-He, P., Liu, Q., Wu, J., Shen, Y. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Proteomic CNS profile of delayed cognitive impairment in mice exposed to gulf war agents.

Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Mice acutely exposed to PB and PER over 10 days showed an increase in anxiety-like behavior, psychomotor problems and delayed cognitive impairment compared to control mice that received vehicle only. Proteomic analysis showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent-exposed mice compared to controls. Proteins associated with the endocrine and immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent-exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways that can be targeted for the development of novel therapeutics against GWI.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Institute targets in on Alzheimer’s

May 7, 2007 – At St. James Hospital in Dublin, Ireland, a nurse is checking the blood pressure of a 62-year-old man. Later, a tech will use a hand-held scanner to measure blood flow in his middle cerebral artery.

The patient has never met Michael Mullan, nor Fiona Crawford. But some 4,150 miles away, they could hardly be happier about his test results.

They show that the man, whose identity is confidential, is showing no adverse reactions to a drug that might be a promising treatment for Alzheimer’s disease.

That is good news for Mullan and Crawford. Directors of the Roskamp Institute, on Whitfield Avenue in southern Manatee County, they are running a clinical trial of Nilvadipine, a drug widely used abroad but not approved in the United States.

The drug is intended to lower blood pressure. But in studies on mice, Roskamp researchers found it also reduced the level of a protein in the brain believed to be at the heart of Alzheimer’s.

The Ireland trial just completed its second phase, a safety study, and the 20 patients taking the drug showed almost no ill effects, paving the way for a broader study.

The clinical trial is the institute’s highest-profile project, but its two dozen scientists also work in fields including drug addiction and head injury.

With even more promising treatments deep in its labs, the little nonprofit academic center is becoming more and more a biotechnology start-up.

Birth of the institute

The institute was born in 1997, but its origins date back another 40 years.

Bob Roskamp was a high school physics teacher. His older brother, diagnosed with schizophrenia, killed himself.

Roskamp tells the story with understatement: “Obviously, it catches your attention in a big way.”

The loss of his brother prompted him to give up teaching and work on opening homes for developmentally disabled adults. He later moved into developing housing communities for seniors.

He began selling his companies — including his Freedom Group to American Retirement Group for $23 million in cash and $14.9 million in stock — leaving him with a question: “What do we do with these surplus dollars?”

The answer is in the logo of the institute bearing his name: “Curing Diseases of the Mind.”

Roskamp and his wife, Diane, are among the pioneers of a style of philanthropy, now more widely followed, of carefully aiming resources at one target and tracking performance.

“Instead of spreading it thinly throughout the world, we would ‘rifle-shot’ it, and have a lot more fun with it,” he said.

Roskamp historically has given the institute about one-third of its operating budget, the rest coming through grants and contracts.

But as federal money has been diverted elsewhere, and the institute’s work has grown more complex, Roskamp has had to pick up more of the tab. He gave just over $1 million in 2005, but $4.6 million this year, he said.

His involvement began with funding a lab at the University of South Florida, then a teaching position eventually filled by Mullan.

In 2003, the institute left the university amid personnel and bureaucratic disputes and moved into the former Bausch & Lomb building in southern Manatee County. Roskamp said university overhead was too expensive, and that scientists can work faster in the independent setting.

“You bring your entrepreneurial hat to this kind of research,” he said. “We’re results-oriented people.”

The scientists appreciate not having to wait for grants and approvals.

“We have the funding from Bob and Diane that allow us to move forward very quickly when we make a new discovery,” Crawford said. “We are really free to focus on the research.”

Paddling mice

Most Alzheimer’s researchers now focus on a protein known as beta-amyloid that forms when a chemical process goes awry. The protein clumps together outside neurons, eventually killing those memory cells.

Mullan and Crawford were part of a team that in 1991 published papers establishing a link between a human gene, on chromosome 21, and early onset of the disease in patients in their 40s and 50s.

A year later, after they came to the United States, they published a paper looking at another genetic link to early-onset Alzheimer’s.

The research made beta-amyloid a prime suspect in Alzheimer’s, and stopping its buildup a potential cure.

Roskamp researchers look for existing drugs and new compounds with that effect. Nilvadipine showed enough promise to test it on lab mice engineered to have Alzheimer’s.

At 10 months, with the disease in full bloom, some mice got the drug while others got a placebo. Later, they scanned the mice’s brains for blood flow.

In the color-coded pictures, the brighter the image, the better the blood flow. The mice getting Nilvadipine scan largely red and orange.

The control animals scan mostly blue-green.

Mullan points to a chart with results of a more traditional test, tracking a mouse’s effort to paddle its way out of a mouse-sized swimming pool.

The mice repeat the test, day after day. Normal mice figure it out and eventually swim a shorter route to the exit.

Mice with Alzheimer’s disease never figure it out, actually taking longer and longer routes.

“But if you give them Nivaldipine, they go from here to here; they do better,” Mullan said, pointing at the figures. “And if you give Nilvadipine to a normal mouse, they do best of all.”

The drug appears to slow or stop the production of beta-amyloid, Mullan said.

As the brain grudgingly yields the mysteries of its architecture, Roskamp’s scientists are exploring how those diseases of the mind may be related by more than just words.

‘Blocking that burst’

In 2002 the institute teamed with the Department of Veterans Affairs to look at memory skills in people who had received traumatic brain injuries.

They found that people who had a gene linked to Alzheimer’s disease recovered less memory function than those without it, even when they had comparable injuries and demographics.

Further research has shown that when the brain suffers such an injury, there is a burst of amyloid production. One theory is that the brain produces the protein as a defense mechanism, but it sometimes overreacts and makes matters worse.

“Blocking that burst appears to be at least one way to try and improve outcomes after head injury,” said Crawford, lead author of the 2002 article.

Last year the Department of Defense approved a $1.5 million grant to the institute to expand that research. It is a particularly urgent matter for the military: Improved body armor is helping soldiers survive explosions — but with little-understood head injuries.

“People can have brain injury even if they didn’t suffer any loss of consciousness, weeks and months of being in the vicinity of an explosive attack,” Crawford said.

For now, that grant is hung up in final reviews.

“We have yet to see dime one,” Roskamp said — but even that $1.5 million pales in comparison with the costs of the Nilvadipine study.

That cuts to the heart of the dilemma scientists face. They might get a moderately effective drug to market quickly, or try to discover the “silver bullet,” which could take many years and exponentially more money.

Roskamp is preparing the foundation to do both.

Just a question of when

To Mullan, the question is not whether there will be treatments for Alzheimer’s.

“It’s the question of when we’re going to get them there,” he said.

It is a question of how effective they will be. Mullan cited three drugs far along in the pipeline, all targeted at reducing amyloid. “They’re not going to be block-busting, perfect drugs by any means, but I think at least two of them will be approved for Alzheimer’s this year.”

Nilvadipine most likely would be like them — useful but not the cure-all. But it offers some advantages.

Developing a new drug from scratch is a much worse bet, Mullan said. Count on 10 to 12 years for development, testing and approvals, with a high failure rate.

“Sometimes they fail spectacularly,” he said, citing Vioxx, a promising drug with unforeseen and deadly side effects.

Nilvadipine, in use for more than a decade, already has a track record for safety. It could help patients while allowing the institute time to find the silver bullet.

By mid-year, the institute hopes to continue the Ireland trial with a double-blind study, meaning neither patients nor doctors know who gets Nilvadipine and who gets a placebo until they conclude. That study, which would involve about 200 people, could cost $20 million, Roskamp said.

Should the drug prove effective, Nilvadipine’s manufacturer could profit — but so would the institute. Because it holds rights to the drug’s newly indicated use, the institute would receive royalty payments, Roskamp said.

The institute has set up a for-profit subsidiary, Roskamp Research LLC, which holds its patents. Roskamp structured it to allow outside backers to support studies, provide the subsidiary with a return on its investment, and guarantee most of the revenue goes to his institute.

“We don’t want to give it to a pharma company, and say here, go make a lot of money off of it,” Roskamp said.

Compounds back in the institute’s labs could provide better returns — and better treatments.

Sarasota’s Roskamp Institute Releases Study Defining a Mechanism for Development of Obesity and the Metabolic Syndrome, Forerunners of Type 2 Diabetes

Sarasota, Fla. – August 1, 2007 The Roskamp Institute released a study defining a mechanism for the development of obesity and the metabolic syndrome, which are the forerunners of type 2 diabetes.  The study, led by Roskamp’s Dr. Robert Farese, is detailed in the August issue of The Journal of Clinical Investigation, a highly prestigious medical research journal.

 

While the Roskamp Institute’s primary focus is on Alzheimer’s disease, Roskamp researchers have a significant interest in diabetes due to studies that suggest those who have diabetes are more likely to develop Alzheimer’s disease.

 

The study found that a deficiency in an enzyme, atypical protein kinase C, impairs the ability of insulin to stimulate glucose uptake into the muscle, which produces a state of resistance to circulating insulin.  Once this occurs, the liver begins to produce excessive quantities of fat, causing abdominal obesity and alterations in blood lipids.  According to the study, this can then lead to obesity and the metabolic syndrome, the precursors of type 2 diabetes.

 

“Although this gene-knockout study was done on mice, it is particularly relevant to type 2 diabetic humans, who are known to have deficiencies of this enzyme in their muscles,” said Dr. Farese.  “The findings showed that in the mice a simple loss of one or more genes that are responsible for the production of this enzyme could eventually cause obesity and the metabolic syndrome which then could lead to type 2 diabetes.”

 

Further research must be done to determine how human diabetics acquire a deficiency of this enzyme in their muscles; however, this mouse model should be especially helpful to further study and devise treatments for obesity and the metabolic syndrome.

 

“We are particularly excited about this study and the potential to develop treatments for obesity and the metabolic syndrome, which are both global health problems,” said Dr. Michael Mullan, director of the Roskamp Institute.  “This study will also be helpful in further determining how obesity, the metabolic syndrome and type 2 diabetes are linked to Alzheimer’s disease.”

 

The study was co-authored by Dr. Farese, who led the team of Mini P. Sajan, Hong Yang, and Sonali Nimal at the Roskamp Institute; and others at the James A. Haley Veterans Administration Medical Center in Tampa; the University of South Florida College of Medicine; the Joslin Research Foundation and Harvard University School of Medicine; Yale University School of Medicine, and Research Center at Oslo, Norway.

 

For more information regarding this study or the Roskamp Institute please visit:

 

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

The Roskamp Institute

The Roskamp Institute, a not-for-profit research Institute, is dedicated to finding cures for neuropsychiatric disorders, with the emphasis on Alzheimer’s disease (AD).  Current research at the Roskamp Institute is focused on dissecting the molecular biological pathways implicated in AD pathogenesis in order to develop therapeutic targets specific to AD etiology. Dr. Michael Mullan (Director of the Roskamp Institute) and Fiona Crawford (Associate director of the Roskamp Institute) were part of the original team that discovered a genetic error called the “Swedish mutation” which results in overproduction of  b-amyloid (Ab) by aberrant proteolytic processing of the amyloid precursor protein (APP). This mutation now forms the bases of most mouse model of Alzheimer’s disease. Previously, the Roskamp Institute published an article in a prestigious scientific journal, Nature, showing that Ab plays a normal role in vasoactive mechanisms but also plays a role in vascular abnormalities and neurodegeneration mediated by free radical. Subsequently, Dr. Daniel Paris, a senior scientist at the Roskamp Institute, discovered that the vasoactive effects of Ab are partly mediated via a pro-inflammatory pathway and showed that this effect of Ab on the vasculature can be blocked by inhibiting specific target molecules.  In order to further understand the role of Ab in the vasculature, Dr. Paris investigated the long term effect of Ab on vascular homeostasis. He then discovered that at low doses, Ab promotes angiogenesis, while at high doses, certain forms of Ab peptides are anti-angiogenic. Collectively, these novel findings resulted in new therapeutic prospects for the treatment of Alzheimer’s disease as well as Cancer.

Researchers at the Roskamp Institute also showed that the presence of functional CD40/CD40L signaling is essential for the full development of AD like pathology in transgenic mouse models of AD. In particular, it was demonstrated that accumulation of cerebral Ab is reduced in transgenic mouse models of AD by genetically or pharmacologically reducing the availability of CD40L to CD40. The Roskamp Institute investigators subsequently revealed that loss of functional CD40L diminishes both APP processing to Ab and microglial activation in the brain (Original findings published in journals Science and Nature Neuroscience). CD40L activated pathways in the presence of Ab appear to mediate both of these effects as well as the hyperphosphorylation of murine tau in vivo at epitopes analogous to those which precede tangle formation of human tau. More recently, Dr. Ghania Ait-Ghezala of the Roskamp Institute showed that CD40/CD40L interaction also affects APP via the NF-kB pathway. Using NF-kB inhibitors and SiRNAs to silence diverse elements of the NF-kB pathway, she demonstrated that reduction in levels of both pathological forms of Ab. These results showed that CD40L stimulation may be a key component in AD pathology and that NF-kB pathway may be suitable targets for therapeutic approaches against AD.

Another major focus of research at the Roskamp Institute includes Traumatic Brain Injury (TBI) Program headed by the Associate Director of the Roskamp Institute. Dr. Crawford and her Roskamp Institute team demonstrated an important relationship between apolipoprotein E (APOE) and memory following TBI. She demonstrated that in Veteran’s with TBI, memory performance was significantly worse in individuals who had at least one copy of APOE ε4 allele than those who did not. She had subsequently been funded through the Veteran’s Administration to further study the relationship between different forms of APOE in TBI with the emphasis on finding treatments for this devastating condition.

Drs. Michael Mullan and Fiona Crawford also received funding by the Counterdrug Technology Assessment Center (CTAC) to evaluate the newly emerged genomics and proteomics technology and find biological markers of substance abuse. Recently, Dr. Crawford’s team showed that cocaine treatment of human progenitor neuronal cells results in increased oxidative stress (possibly mediated by inflammatory responses) which precedes cell death. Thus, these findings may have implications for the consequences of cocaine abuse in situations where antioxidant capacity is compromised, as in the aging brain.

As evident here, the Roskamp Institute team has been a pioneer in many area of research in neuropsychiatric diseases and will continue to do so to find novel therapies for these disorders. Currently, a new clinical trial based on the discoveries made at the Roskamp Institute is underway to assess safety and efficacy of nilvadipine in treatment of Alzheimer’s disease. Through the generous support of Diane and Robert Roskamp, the Veteran’s Administration, the National Institutes of Health, CTAC and the Department of Defense, the Roskamp Institute will continue to provide potential avenues for novel therapeutic interventions for neuropsychiatric disorders.

 

for more information on the Roskamp Institute please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Roskamp Institute on Gulf War Illness

The Roskamp Institute located in Sarasota, Florida is the leading research center in the area.  The research focuses on neurological diseases that affect young and elderly men and women of this world. Some of the main focuses are Alzheimer’s disease, addiction, post-traumatic stress disorder (PTSD), multiple scoliosis, Gulf War syndrome and many more. The Director Dr. Michael Mullan leads his team of researchers to exciting findings. Recently the Institute has been given a grant from the VA for their research involving Gulf War Illness. This Illness that inflicts the soldiers that fought during the Gulf War affects their motor skills, memory, stability and other problematic symptoms. How the Illness commenced was through the combination of the neurotoxins and pesticides given to the soldiers. The research done in the Institute led to the finding that shows the toxic mixture affects the long fatty acid chains within the brain. Research continues within the walls of the 42,000 sq. ft research facility hopefully terminating the life altering Illness for our Veterans.

 

for more information on the Roskamp Institute please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

The Roskamp Institute Battles Drug Abuse

A National Survey on drug abuse in America reported in 2004 that about 34 million Americans are currently using or have been exposed to cocaine at some point in their lifetime. Cocaine is highly addictive and affects individuals along with their families. The cost of health care services has risen due to the increasing use of cocaine. Currently, the Roskamp Institute is involved in research to discover a treatment for substance abuse. Dr. Michael Mullan MD, PhD is the director of the Roskamp Institute and has worked vigorously on addiction and has found that addictive disorders have a significant genetic component. These genetic components play a key role in drug abuse.

The Roskamp Institute scientists have previously shown that a genetic change called polymorphism in a gene for an opioid receptor in the brain is a risk factor for alcohol dependency. With this information, the Roskamp Institute researchers then examined the frequencies of this polymorphism carrying genotypes and alleles in numerous groups of individuals addicted to the substance versus individuals with no history of addiction to the substance. These Roskamp Institute scientists found that the mu-opioid receptor’s polymorphism is a genetic risk factor for substance dependence but not to any particular type of drug. Meaning, an individual with this polymorphism is more likely to become addicted to a substance than an individual without it. The Roskamp Institute previously published these findings in the journal Molecular Psychiatry.

Dr. Mullan and Dr. Crawford along with the other researchers at the Roskamp Institute received an award from the Counter drug Technology Assessment Center (CTAC), to continue their work on drug addiction.

Affymetrix is a name of the company which provides the Roskamp Institute with the genetic software that is used by scientists who study genetics (genomics). The Roskamp Institute used genomics technology in order to find the cocaine’s affects on the brain cells known as neuronal cells.  The Roskamp Institute scientists continue to research projects which are focused on the inflammatory and immune responses to cocaine.  The Roskamp Institute scientists showed that these responses also results from the exposure of the neuronal cells to cocaine and these responses are also time dependant. These findings, originally published in the Journal of Neurochemistry, illustrate that there are biological and physical consequences of cocaine addiction.

The Roskamp Institute researchers are currently working on studies involving oxidative stress in the brain.  This oxidative stress can also be caused by excessive use of cocaine and is hypothesized to result in permanent brain damage.  With such experiments in progress, the Roskamp Institute is a good candidate for additional government funding and  these discoveries will be useful towards the battle against drug abuse in form of treatments.

The Traumatic Brain Injury Program at the Roskamp Institute

Among the soldiers who survive conflicts in Iraq and Afghanistan, the traumatic brain injuries account for a larger proportion of their casualties than in any other US war in recent history. According to the Joint Theater Trauma Registry, established by the U.S. Army Institute of Surgical Research, approximately 22 percent of the injured US soldiers received injuries to the head, face, or neck. A major reason for this high ratio of these injuries is Kevlar body armor and helmets. Although, it successfully protects these soldiers from bullets and shrapnel exposure,Kevlar helmets cannot fully protect theface, head, and neck areas. Additionally, it is also unsuccessful in preventing the closedbrain injuries produced by blasts. Furthermore, among patients evaluated at Walter Reed hospital, closed head injuries outnumber other penetrating injuries (originally published in New England Journal of Medicine).

Most individuals with a mild traumatic brain injury improve entirely within a year,but moderate and severe brain injuries are more complex and have long-term consequences. The Center of disease Control and Prevention estimated that 5.3 million Americans are living with disabilities resulting from traumatic brain injury. Dr. Michael Mullan (Director of the Roskamp Institute) Dr. Fiona Crawford (Associate Director of the Roskamp Institute) and their team of scientists previously demonstrated that apolipoprotein E (APOE) influences traumatic brain injury outcomes. These Roskamp Institute scientists examined 110 participants from the Defense and Veterans’ Head Injury Program to determine a relationship between APOE genotype and memory performance on certain cognitive tests administered to these head injured soldiers. The memory performance was much worse in soldiers who had at least had one APOE epsilon 4 allele compared to those who did not. This Roskamp Institute team also determined that these findings were limited to memory and not other cognitive performances such as executive functioning. Therefore, these data support a specific role for the APOE protein in memory outcome following TBI, and suggest an APOE isoform-specific effect on neuronal repair processes (originally published in the journal Neurology).

Dr. Fiona Crawford received a Merit award from the Veteran’s Administration to further study, using genomics technology, the role of APOE in Traumatic Brain Injury. Dr. Fiona Crawford and her Roskamp Institute team have now completed the experiments showing differences in genomics response among the different mouse models after traumatic brain injury.  Recently, Drs. Michael Mullan and Fiona Crawford received a prestigious award of $1.5 million from the Department of Defense which will allow the Roskamp Institute to investigate ApoE and other proteins to find potential peripheral biological markers and novel therapeutic treatments for traumatic brain injury. Florida Senator Bill Nelson recently toured the Roskamp Institute to observe its traumatic brain injury program in support of the soldiers affected by this devastating condition.

The Roskamp Institute is a world-renowned state-of-the-art research and clinical facility located in Sarasota Florida dedicating to finding novel therapeutics for treatment of neuropsychiatric disorder, especially Alzheimer’s disease, traumatic brain injury and substance abuse. The Roskamp Institute is supported by the funding from government agencies such the National Institutes of Health, the Veteran’s Administration and the Department of Defense as well as private donations from the Robert and Diane Roskamp Foundation.

for more information on Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Roskamp Institute finds one of the genetic causes for Tourettes syndrome

Tourette syndrome (TS) is a heterogeneous childhood disorder and occurs with a frequency of approximately four to ten per 10,000 in the general population (Mason et al. 1998). The symptoms for Tourette syndrome include multiple motor and one or more vocal tics. These symptoms appear to overlap with other neurobehavioral disorders such as obsessive-compulsive disorder, attention deficit/hyperactivity disorder, mood disorders and learning disorders. The origin of Tourette syndrome is not clearly understood at this time. However, there appears to be presence of a genetic component, evidence for which comes from both family and twin studies. Furthermore, a complex mode of inheritance has been suggested which probably involves several genes with different effect size.  Additionally, environmental factors such as prenatal and birth complications may also influence the disease manifestation.

The Roskamp Institute scientists Drs. Michael Mullan (Director of the Roskamp Institute), Fiona Crawford (Associate Director of the Roskamp Institute) and Ghania Ait-ghezala (a senior scientist at the Roskamp Institute) have previously shown that among patients diagnosed with Tourettes syndrome in two unrelated families, there appears to be a breakage and translocation on chromosome 8 (original findings published in the journal Human Genetics).  Drs. Fiona Crawford and Ghania Ait-ghezala subsequently received funding from the Tourettes syndrome association to further characterize this chromosomal breakage.

Currently, there is no treatment available for Tourettes syndrome. Although, the symptoms in most individuals improve by the late teens and early 20s, this disorder is generally lifelong and chronic.  Studies have also shown that although symptoms such as tics may disappear after the childhood period, it is possible that other psychiatric disorders such as depression, panic attacks, mood swings, and antisocial behaviors persist and cause lifelong impairment in adults.  Therefore, a treatment for this disorder is much needed so that a child can actually be disease free throughout his/her life and has a decent chance of living a normal life. The Roskamp Institute is currently engaged in molecular biological research aimed at determining the genes that are disturbed when this chromosomal breakage and translocation occur. Through this novel finding, the scientists at the Roskamp Institute hope to discover a treatment for Tourettes syndrome.

The Roskamp Institute is located in Sarasota Florida and is a not-for-profit stand alone research institute dedicated to finding cures for neuropsychiatric disorders. The Roskamp Institute is currently conducting a clinical trial evaluating safely and efficacy of nilvadipine for the treatment for Alzheimer’s disease (clinical trial being performed in Dublin, Ireland). Furthermore, the Roskamp Institute is conducting various molecular biological studies to find treatment for chronic diseases such as cancer, diabetes, and other neuropsychiatric disorders such as traumatic brain injury, gulf war syndrome, and substance abuse. The Roskamp Institute operates two memory disorder clinics located in Sarasota and Tampa, Florida. These clinics conduct diagnostic assessments for memory disorders and conduct industry and government funded clinical trials in several neurological and neuropsychiatric disorders. The Roskamp institute is currently funded by the National Institutes of Health, the Veteran’s Administration, the Department of Defense and the private donation by the Robert and Diane Roskamp foundation. For more information or the research or clinical trials, please contact us at 94-752-2949.

Sarasota’s Roskamp Institute Welcomes U.S. Senator Bill Nelson

August 21, 2007

Sarasota, Fla. – The Roskamp Institute today welcomed U.S. Senator Bill Nelson to its research facility in Sarasota, Florida, where the Senator toured the laboratories and discussed the various types of research currently being conducted at the Institute.

 

“We thank Senator Nelson for his interest in our research and for coming to the Institute to tour our lab and view our good work first hand,” said Dr. Michael Mullan, director of the Roskamp Institute.  “We are proud of the research our Institute has done and look forward to continuing in our quest to better understand and ultimately cure debilitating diseases of the mind.”

 

While Senator Nelson’s visit was mainly to discuss with the researchers the current and future research being done in relations to Traumatic Brain Injury, the Roskamp Institute is devoted to understanding the causes of and finding cures for various neuropsychiatric and neurodegenerative disorders and addictions.  Specifically, the Institute utilizes a broad range of scientific approaches to understand the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease.

 

“We currently have 45 scientists and 10 clinicians with eight active clinical trials in the field with several more on the horizon,” Dr. Mullan continued.  “It is vital that we are persistent in our pursuit to help Florida’s sufferers and their families and we are glad Senator Nelson is here to share in our goal.”

 

The Roskamp Institute has built its esteemed reputation amongst the research community and has been heralded for its achievements including:

 

  • Being the first Florida-based Alzheimer’s Research Institute (and one of only a handful of Institutes worldwide) to conduct a human clinical trial with a drug discovered by its own research.
  • Discovering a new class of drugs that lower the production of the main pathological protein that causes Alzheimer’s disease.
  • Applying state of the art technologies (proteomics and genomics) to find early diagnostic markers for Alzheimer’s disease.

Extensive participation from Florida residents in the Institute’s leading edge Alzheimer’s research program.

for more information on Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Dr. Mullan’s Alzheimer Research Offers Invaluable Insights On The Disease

Millions of people across the globe suffer from Alzheimer’s disease. It is estimated (Alzheimer’s Association, 2008) that in every 71 seconds someone from the US develops Alzheimer’s disease, and estimations by mid-century shows that the probability of someone developing Alzheimer’s disease is every 33 seconds. At present, there are approximately 5.2 million Americans in all age groups who suffer from Alzheimer’s disease; and 13% of these patients fall in the age category of 65 years and older. It is calculated that by 2050 the number of Alzheimer’s patients falling in the age category of 65 years and older will increase to a range of over 11 million to 16 million alone (Alzheimer’s Association, 2008). The facts and figures are alarming and bring our focus to the unmet demand for effective therapeutics and new researches for treatments related to Alzheimer’s disease.

Dr. Michael Mullan is an accredited professional from biomedical field. He has extensively researched on the causes and prospective cures of Alzheimer’s disease and other neurodegenerative disorders conditions. Based in Sarasota, Florida, he is reputed Director of Roskamp Institute. He is a highly qualified professional and has dedicated his time to finding cures for neuropsychiatric and neurodegenerative disorders and addictions. Dr. Mullan’s Alzheimer research work has provided invaluable insights on the disease with which many potential cures have been developed and tested. Dr. Mullan’s Alzheimer research indicates that one of the causes directly related to the disease is the excess accumulation of beta-amyloid, a type of protein, present in the brain. It was estimated that the protein is produced in every human but its excess accumulation can result in Alzheimer’s. Besides, Dr. Mullan’s Alzheimer research continuously tests medications and therapeutic treatments to help slow down the accumulation of beta-amyloid and related inflammation in patients.

About Dr Michael Mullan

Dr Michael Mullan has been working in the biomedical field for many years. He is a leading researcher with special expertise in assessment of the earliest cognitive symptoms and stages of Alzheimer’s disease. Mullan’s Alzheimer research works are also published in various articles which help students and researchers for making new discoveries. Find out more about his Alzheimer research works, by browsing through www.rfdn.org or www.mullanalzheimer.com or www.mullanalzheimer.info.

Dr. Mullan’s Alzheimer Research Identified Various Genetic Variations

Based in Sarasota, Florida, The Roskamp Institute is a not-for-profit organization. It has dedicated time to finding cures for several neuropsychiatric disorders with a special emphasis on Alzheimer’s disease (AD). In order to develop therapeutic targets which are specific to Alzheimer’s disease etiology, the scientists engaged in current research at Roskamp Institute focus on dissecting the molecular biological pathways which are associated in Alzheimer’s disease pathogenesis.

Dr. Michael Mullan is the Director of the Roskamp Institute, and along with his team, he discovered the concept of ‘Swedish mutation’, a genetic error which results in overproduction of beta-amyloid by aberrant proteolytic processing of amyloid precursor protein (APP).  The concept of Swedish mutation now forms the bases of most mouse model of Alzheimer’s disease. Many tests and findings by the Roskamp Institute resulted in several therapeutic prospects for the treatment of Alzheimer’s disease as well as Cancer.

The Roskamp Institute has contributed greatly by providing research on the treatments of several neuropsychiatric disorders like traumatic brain injury, substance abuse, and Alzheimer, etc. With the guidance and knowledge provided by Dr. Mullan, the institute tested many causes and correlations between Alzheimer’s disease and proteins present in human brain. With Dr. Mullan’s Alzheimer research, several types of genetic variations, which can be the cause of Alzheimer’s, have been identified. It was discovered that the central reason to the disease process is a small protein identified as the ß (beta)-amyloid. Although, this protein is present normally in the human brain, but at times excess or abnormal accumulation can result in Alzheimer’s disease. With Dr. Mullan’s Alzheimer research, the institute tests cutting edge cures, therapeutic treatments and medications to slow down the process of toxic ß-amyloid accumulation.

Dr Mullan’s Alzheimer research proves that Aβ peptide prevents blood vessel growth and eventually inhibits tumor growth in brain. To identify if Aβ has the same effect with short derivatives, he studied various sequences within the Alzheimer’s Aβ peptide which have potential therapeutic relevance in preventing tumor growth. Dr. Mullan’s Alzheimer research work has contributed exceptionally to the field to help understand the disease and find its cures. Find out more about his Alzheimer research works, by browsing through www.rfdn.org or www.mullanalzheimer.com or www.mullanalzheimer.info.

Family History of Alzheimer’s disease – what does it mean?

Frequently in the Roskamp institute Memory Clinic we are asked what a family history of Alzheimer’s disease means for the children and other blood relatives of sufferers.  Although this question is always handled on an individual basis there are some general guidelines that can be offered to access risk for the disease to children and other family members related to a sufferer.  Naturally, family members who perceive they are at risk for developing the disease themselves may suffer from a great degree of anxiety it is therefore important to ask the staff at the Roskamp Institute what the individual risk is for developing the disease.  In general the genetic risk for Alzheimer’s disease can be divided into two categories; early onset familial disease which is highly genetic and occurs in families which may have onsets of the disease in the 40s,50s or 60s;  late onset disease which is frequently familial but where the disease onsets in the seventh decade onwards.  We shall consider these two scenarios separately.

Early onset Alzheimer’s disease.

The term “early onset Alzheimer’s” is frequently misunderstood or used in a confusing way.  What we generally mean by  early onset Alzheimer’s is Alzheimer’s that onsets before the age to 60 years.  This is in contrast to the term early onset as referencing the early stage of the disease.  This is a confusing way to use the term and is discouraged.  Early stage disease is a better term to describe the early phases of the disease. Early onset familial disease occurs in families that are affected in multiple generations by mutations in genes that can trigger the disease.  Families of early onset disease thankfully are very rare but they have provided great insight into the disease process probably in all cases of the disease (early and late onset).  Sadly, frequently in these families the disease is inherited in what is known as an autosomal dominant fashion.  Autosomal dominant inheritance means that 50% of the offspring of each generation on average are impacted by the disease.  Some generations may be very fortunate and although they may be at risk for inheriting the diseased gene from one or the other parent none of the siblings in a sibship may be affected.  On the contrary sibships can be very unlucky in which case more than 50% are impacted with the disease.  For each child of an affected parent there is a 50% chance of inheriting the disease and this chance is not influenced by whether other siblings have already inherited the disease or not.

Unfortunately the inheritance of these rare genetic variance means that individuals at risk are highly likely to develop the disease if they live long enough.  One of the important characteristics of these familial mutations is that the disease tends to onset around approximately the same time of life.  Thus if a family has a mean (average) age of onset of 52 and one inherits one of these rare generic  errors then one is unlikely to live to 60 without developing  signs or symptoms of the disease.  By contrast if one does not carry the mutation then there is no more risk for the disease than the general population.

Again it is most important to emphasize that such families are extremely rare and early onset Alzheimer’s is not the most likely reason for patients or their families to visit the Roskamp Institute Clinic.  In fact, approximately 1% or less of cases of Alzheimer’s Disease have what can be described as early onset disease.  In the past, individuals who come from such families have sought genetic counseling including genetic testing for these genetic errors.  It is relatively straightforward to detect such errors but clearly the genetic information is highly sensitive.  Family members should therefore think very carefully before seeking such information however initially finding out more about early onset disease is a recommended step.

Clinicians at the Roskamp Institute are happy to discuss early onset disease with patients and their families as they wish.  Finally it should be noted that many cases of early onset disease occur without a family history.  Thus individuals can manifest the disease before the age of 60 but have no other known family members either in the prior generations or in subsequent generations that develop the disease the cause of early onset Alzheimer’s that is not familial is not well understood but importantly there is no risk to subsequent family members for development of the disease.

Late onset (common) Alzheimer’s disease.  Much more commonly patients and their families come to the clinic at the Roskamp Institute and seek advice on the inheritance of Alzheimer’s when one or more members of the family has late onset disease.  This is defined as disease which onsets over the age of 60 and this is by far in a way the most common cause of the disease. It is estimated that approximately 4 million Americans presently either have the disease or are in the early or pre clinical stages – most of these cases are late onset Alzheimer’s Disease.  The predicted numbers for future disease prevalence are very high. For instance it is estimated that by mid century there could be as many as two hundred million individuals afflicted with the disease.

Most late onset Alzheimer’s disease does not exhibit a clear autosomal dominant pattern meaning that the risk to offspring of individuals suffering with the disease is usually considerably less than 50%.  Certain genetic risk factors for late onset disease have been identified – the most important of which is apolipoprotein E (APOE).  There are 3 common forms of APOE: E2, E3 and E4.  The discovery by Allen Roses and his colleagues at Duke University showed that Alzheimer’s disease sufferers were much more likely to carry one or two copies of the E4 allele (genetic form) of APOE than the normal population.  Carrying one copy of APOE 4 increases ones risk for the disease by approximately three times and carrying two copies can increase the risk for the disease by up to fifteen times compared to individuals who do not carry an APOE 4 allele.

Many family members express interest in being genetically tested for their risk for the disease.  Such tests are commercially available but most centers discourage the use of testing prior to symptoms because many individuals who carry an APOE 4 allele do not necessarily develop the disease at least until late old age.  Conversely it’s very possible to develop Alzheimer’s disease without carrying an APOE 4 allele. Therefore on an individual basis the test is not overly helpful in specifying who may or may not develop the disease.  However on a group basis APOE genetic testing is very helpful to give an average estimate of the numbers of individuals who will subsequently develop Alzheimer’s.

It is anticipated that as better treatments are available for Alzheimer’s disease there will be greater interest in genetic testing.  For instance it is expected that as treatments are used earlier and earlier in the stages of the disease that individuals in the very early stage or maybe with no symptoms at all might seek medical treatment once such treatment has been established as effective in stopping the rate of progression or disease onset.

Despite the fact that genetic testing is not used frequently in clinical practice it is a tremendous tool in assisting researchers in understanding when and why the diseases develops and in planning clinical trials to take into account who is most likely to develop the disease.  Already there is evidence from several clinical trials that individuals that carry the APOE 4 allele may be more refractory to certain treatments.  As drug development progresses it will be important to develop medications that are able to tackle the severest form of the disease i.e. those patients who are carrying and APOE 4 allele.

Summary:   The two types of familial Alzheimer’s disease differ in the risk for offspring of developing the disease.  The early onset cases as noted have children that are highly at risk for developing the disease if there is a family history.  By contrast late onset disease or low clustering in families is much less genetically predisposed.  In both cases genetic tests are available but are generally discouraged particularly for late onset disease.  Roskamp Institute researchers and clinicians are well versed in the genetic aspects of the disease and can advise on an individual or family basis as required.

The Roskamp Institute is a not-for-profit research Institute located in Sarasota and Tampa, Florida, that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders and addictions with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinics also offer comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

By Dr. Michael Mullan, Director of Alzheimer Research Institute, The Roskamp Institute

for more information on Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

Why work with Alzheimer’s disease patients?

Walking into the Memory Disorder Clinic at the Roskamp Institute one might ask “Why work with Alzheimer’s patients and their families?”  The answers are manyfold.  One of the most rewarding aspects of working with Alzheimer’s patients is that they are most commonly our oldest citizens who have 60, 70 or 80 years of life experience behind them  many of them have served their country in one form or another  - frequently in the military but often times in businesses working for others or their own companies.  Many of those serving in the armed forces have captivating stories.  One visitor to the clinic had parachuted into three war zones Normandy, the “boot” of Italy, and Germany.  Remembering this tale this gentleman was most afraid of being shot by the Russians!  Of course being able to recall these old memories is not unusual for Alzheimer disease suffers.  In fact the tendency to reminisce sometimes becomes a prominent feature of the disorder.  Most caregivers are initially concerned by another aspect of the disorder namely the forgetfulness for recently acquired or presented information.  Such things as recent visits recent phone calls or recent conversations and events may not be remembered either in part or in full.  This distressing symptom interferes with social activities and is a progressive aspect of the disease.  Therefore one of the most rewarding aspect of working with Alzheimer’s sufferers and their families is being able to convey to them the several treatment options that are available.  This includes, as well as those drugs approved by the FDA, new and experimental treatments including those that are being developed by the Roskamp Institute itself.  

Providing hope for patients and their families is a critical part of interfacing with them.  In addition helping families to come to terms with a disorder  that can impact many aspects of  their love ones’ lives (including social interactions, pastimes and sports, financial transactions and medical legal issues) enables families to make the necessary adjustments  to deal with the condition.  Naturally a particularly satisfying interaction can occur when certain elements of a patient’s health can be altered to improve the outcome once a diagnosis of Alzheimer’s has been made.  For instance we know that cardio-vascular health interacts critically with Alzheimer’s disease and aversion of cerebrovascular events (such as small strokes or transient ischemic attacks) has a highly beneficial effect on the outcome of Alzheimer’s patients.  In addition other conditions such as diabetes or thyroid disease can interact negatively with the disease.  These and many other treatable causes of cognitive dysfunction appear at the Roskamp Memory Clinic and are regularly amenable to intervention.  Sometimes previous diagnoses are found to be incorrect and memory loss may be completely reversible.  For instance people suffering from normal pressure hydrocephalus have a condition that is completely amenable to surgical correction.

Another gratifying aspect of working with Alzheimer’s patients is being able to give their families and loved ones a clear indication of what the treatment options are and what the outcomes are likely to be.  In addition family members are often concerned about their own risk for developing the disease it now being common knowledge that the disease has a familial aspect.

All in all there is much to recommend a profession working and caring for Alzheimer’s patients. Our elderly are frequently amongst our most valued citizens who have contributed to the prosperity and safety of subsequent generations.  Continuing to work for their immediate care and finding new treatments to improve their long term prognosis are the premier interests of the Roskamp Institute’s researchers, physicians and clinicians.

Alzheimer’s disease drug developed at Roskamp Institute approved for key clinical trial funding in Europe

Nilvadipine, an Alzheimer’s drug developed at the Roskamp Institute in Sarasota announced earlier this year was selected for funding or a large-scale European clinical trial. An international research consortium led by Trinity College Dublin (Ireland) announced more than 500 patients will participate in the multicenter Phase III clinical trial designed to study the effectiveness of Nilvadipine.

Michael Mullan, M.D., Ph.D., Roskamp Institute director who, with associate director Fiona Crawford, Ph.D and lead scientist Daniel Paris, Ph.D., led the research team that developed the drug. Mullan said, “We need many more medicines to move forward into advanced clinical trials in the fight against Alzheimer’s Disease and we are pleased the Roskamp institute has played such a major role in the development of this drug.” Before a drug can move into clinical practice, Phase III is usually the last step in the regulatory process.

The clinical trials will take place in Europe, where Brian Lawlor, M.D., Connolly Norman Professor of Old Age Psychiatry at Trinity College Dublin, Ireland, will be principal investigator and coordinator. The study will be funded by the European Commission Seventh Framework Programme and more than 20 European clinical sites will participate. Nilvadipine is already approved for the use in mild cases of hypertension (high blood pressure) and Mullan says, “The process can move more quickly in Europe, and the study findings may help accelerate the process with the U.S food and Drug Administration (FDA).

Mullan and Crawford have been studying Alzheimer’s disease for more than 20 years, moving from the UK to Florida in 1991 and to Sarasota in 2003 to establish the Roskamp Institute. “Some of our recent studies have involved Sarasota area residents, who have contributed to our understanding of Alzheimer’s disease and helped move the development process forward,” said Crawford. Now, the Roskamp Institute will provide research support for the Phase III clinical trial, such as assessing genetic and other markers for Alzheimer’s disease in study participants.

For more information on Alzheimer’s Disease please visit www.mullanalzheimer.com

Or http://mullanalzheimer.info

Or www.rfdn.org

Roskamp institute studies may lead to better diagnosis

Researchers at the Roskamp Institute have new studies that could lead to better diagnosis and eventual treatment for U.S. military personnel as well as other patients with TBI, commonly known as traumatic brain injuries.

Fiona Crawford, Ph.D., associate director of the Institute, a leading research facility for Alzheimer’s disease and other neurological disorders says, “We have found that there are changes in blood proteins that occur after a head injury, and that these are dependent on the severity of the injury, the time since the injury and genetic factors influencing outcomes after head injury.” Crawford’s research indicates that TBI can affect cellular mechanisms in the brain long after the original trauma, and that blood biomarkers reflect these ongoing processes. She also stated, “Translating these finding from the laboratory to human patients may help clinicians determine the extent of the brain injury, how long ago the injury occurred and the patient’s prognosis for a favorable or a poor outcome.”

Traumatic brain injury has multiple consequences at the cellular level and so molecular changes can persist for weeks and months after the initial brain swelling and other immediate issues have resolved. Crawford says, “Identifying blood biomarkers of mild TBI would improve medical management by enabling us to identify patients who need treatment or intervention, even if they do not have obvious signs of a brain injury.” The U.S. Department of Defense, and the Veterans Administration supports all of Crawford’s work because it could lead to better diagnosis of military personnel with mild brain injuries and better long-term care of our veterans.

For more information on Alzheimer’s Disease please visit www.mullanalzheimer.com

Or http://mullanalzheimer.info

Or www.rfdn.org

Research Highlights The Direct Causes Related To The Disease

Alzheimer’s disease affects patients over 65 years of age and is classified as a type of dementia. However, the less prevalent early-onset Alzheimer’s can also occur earlier than 65 years of age as shown by several researches. As per the 2006 statistics, there were 26.6 million patients of Alzheimer’s and it is estimated that the disease will affect 1 in 85 people globally by 2050. Presently, there are no cures available for the disease and it is estimated to get worse with age gradually leading to death. Alzheimer’s is calculated to affect a person’s memory, affects the ability to learn and also types of behavioral changes.
Dr. Michael Mullan is a highly accredited biomedical professional and has contributed vastly to the field of research on neurodegenerative disorders conditions such as Alzheimer’s disease. He is chaired as the Director at Roskamp Institute. He is based in Sarasota, Florida, and is exceptionally qualified in finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Roskamp Institute utilizes superior scientific approaches along with Dr. Mullan to understand the root causes and potential therapies of disorders such as Alzheimer’s disease. Aside researching on Alzheimer’s, the institute has successfully studied other illnesses and disorders such as Gulf War Illness, Brain Research, etc.
With Dr. Mullan’s Alzheimer research, science has come to a better understanding of the disease and of developing its prospective cures. Dr. Mullan’s Alzheimer research proves that one of the direct causes related to the disease is the excess accumulation of beta-amyloid which is a type of protein in the brain. It is noticed that the protein is produced in every human, but its excess accumulation can result in Alzheimer’s. Along with the team, Dr. Mullan’s Alzheimer research has tested many medications and therapeutic treatments to help slowing down the accumulation of beta-amyloid and associated inflammation.
About Dr Michael Mullan
Dr Michael Mullan has been working in the biomedical field for many years. He is a leading researcher with special expertise in assessment of the earliest cognitive symptoms and stages of Alzheimer’s disease. Mullan’s Alzheimer research works are also published in various articles which help students and researchers for making new discoveries. Find out more about his Alzheimer research works, by browsing through www.rfdn.org or www.mullanalzheimer.com or www.mullanalzheimer.info.

Dr. Mullan’s Alzheimer Research Involved Studying Brain Proteins

The Roskamp Institute has surfaced as a leading and reputable non-for-profit biomedical research organization. It has successfully experimented to find cures for several neurodegenerative disorders and conditions like Alzheimer’s disease. Through the clinical trials division and outpatient clinic, at the institute, thousands of Alzheimer’s patients get superior services and therapeutic treatments. Dr. Michael Mullan is the Director of Roskamp Institute. Dr. Mullan is an experienced and a competent individual. His research efforts led to the identification of Swiss Mutation.
Along with Dr. Mullan, the institute has helped in contributing to provide insights on the treatments of neuropsychiatric disorders such as Alzheimer, traumatic brain injury, substance abuse, etc. through unparalleled research. Under the supervision and guidance of Dr. Michael Mullan, several causes and cures related to Alzheimer’s disease have been found. Dr. Mullan’s Alzheimer research identified various types of genetic variations which may be the cause of predispose humans to this disease. His research and study identified that the central reason to the disease process is a small protein known as ß (beta)-amyloid. The excess and abnormal accumulation of ß-amyloid in the brain results in Alzheimer’s disease. With Dr. Mullan’s Alzheimer research, cutting edge cures, medications, and therapeutic treatments are tested and developed to help slow down the process of ß-amyloid’s toxic accumulation.
As per the research on Dr Mullan’s Alzheimer, Aβ peptide is responsible for preventing blood vessel growth and inhibiting tumor growth. He studied several particular sequences within the Alzheimer’s Aβ peptide to identify if Aβ can have the same effect with short derivatives as well. The research proved that the peptide has potential therapeutic relevance to prevent the growth of tumor. The research involved conducting clinical trials which are specifically conducted to developing superior treatments for neurodegenerative diseases. In order to understand the diseases and finding its causes and prevention, Dr. Mullan’s Alzheimer research work has contributed extraordinarily in the field. Furthermore, with his constant efforts and guidance, the Roskamp Institute was also able to carry out research in neuropsychiatric disorders such as Traumatic Brain Research, Gulf War Illness, and Alzheimer’s. Find out more about his Alzheimer research works, by browsing through www.rfdn.org or www.mullanalzheimer.com or www.mullanalzheimer.info.

Event: Journal Club “Disrupted-in-Schizophrenia-1 expression is regulated by β-site amyloid precursor protein cleaving enzyme-1–neuregulin cascade”

Laila Abdullah will be presenting the paper on Friday (7/2/2010) at Roskamp Institute.

Title:Disrupted-in-Schizophrenia-1 expression is regulated by β-site amyloid precursor protein cleaving enzyme-1–neuregulin cascade

Journal: PNAS

5622–5627 | March 23, 2010 | vol. 107 | no. 12

Journal Club is held every Friday between 4 Pm-5pm. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Event: Journal Club “The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease”

Nowell (Jim) Ganey will be presenting the paper on Friday (6/25/2010) at Roskamp Institute.

Title:The effect of encapsulated VEGF-secreting cells on brain amyloid load and behavioral impairment in a mouse model of Alzheimer’s disease.

Journal : Biomaterials.

2010 Jul;31(21):5608-18. Epub 2010 Apr 28.

Journal Club is held every Friday between 4 Pm-5pm. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949


News:Nomination for Business/Education Partnership Award through the School District of Manatee County’s ePIE program

The Roskamp Institute has been nominated for a Business/Education Partnership Award through the School District of Manatee County‘s ePIE program. Since 1990, this awards program recognizes businesses, organizations, and individuals who have made the commitment to work together to enhance education in the School District of Manatee County. The awards ceremony will be held in August.  Last year 2009  the Roskamp Institute won a Business/Education partnership award for its work with South East High School.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

News:Roskamp Institute was recognized by the South East High School Technical Student association for partnering will the in a diabetes project

On Tuesday June 15th the Roskamp Institute was recognized by the South East High School  Technical Student association for partnering will the in a diabetes project.  At the Victory celebration banquet held at South East High following the TSA teams success in the State TSA finals. The Diabetes project was awarded second place in the medical visualization category.  The project will be used in the National Finals which are being held in Baltimore on June 27th.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

News: FDA advisory committee unanimously recommends approval of Novartis investigational treatment FTY720 to treat relapsing remitting MS

The Roskamp Institute continues to actively recruit clinical research participants for the treatment of both Alzheimer’s disease and Multiple sclerosis. We are proud to share the following press announcement regarding a clinical trial/potential treatment that Roskamp Institute has been involved in since 2006: “FDA advisory committee unanimously recommends approval of Novartis investigational treatment FTY720 to treat relapsing remitting MS”.

The Roskamp Institute Memory Clinic and Clinical Trials Division provide a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941) 256-8018.

Event: Journal Club “NF-jB activity affects learning in aversive tasks: Possible actions via modulation of the stress axis”

Scott Ferguson will be presenting the paper on Friday (6/18/2010) at Roskamp Institute.

Title:NF-κB activity affects learning in aversive tasks: Possible actions via modulation of the stress axis

Journal: Brain, Behavior, and Immunity

doi:10.1016/j.bbi.2010.04.005

Journal Club is held every Friday between 4 Pm-5pm. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

APOLIPOPROTEIN E GENOTYPE AND OXIDATIVE STRESS RESPONSE TO TRAUMATIC BRAIN INJURY

By S. FERGUSON,a* B. MOUZON,a G. KAYIHAN, a M. WOOD, a F. POON, a S. DOORE, a V. MATHURA, a

J. HUMPHREY, a B. O’STEEN, b R. HAYES, c A. ROSES, d M. MULLANa AND F. CRAWFORDa

aThe Roskamp Institute, 2040 Whitfield Avenue, 34243, Sarasota, FL,

USA

bCenter for Traumatic Brain Injury Studies, McKnight Brain Institute of

the University of Florida, 100 Newell Drive, Gainesville, FL, USA

cBanyan Biomarkers, 12085 Research Drive, 32615, Alachua, FL,

USA dR. David Thomas Executive Training Center, Duke University, One

Science Drive, Suite 342, Durham, NC, USA

Abstract—Traumatic Brain Injury (TBI) is known to result in oxidative stress, which is an increase or imbalance in the amount of cytotoxic oxidants and free radicals beyond what the cell can normally handle.  The Apolipoprotein E (APOE) gene has different variations called alleles, with two of the most common known as APOE3 and APOE4.  The different APOE alleles have been shown to influence outcome following TBI in different ways, with the APOE4 allele being associated with poor outcome, but through as yet unclear mechanisms, so we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI.  Mice transgenic for either human APOE3 or APOE4 on a murine APOE-deficient background were examined in an approved model of TBI. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray (“gene chip”) analysis was performed on individual samples from three mice per group to determine the way different genes are turned on or off in response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for the ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect  injury has on the oxidative stress level compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype specific differences of outcome following TBI.

To reach the article that was published in Neuroscience Volume 168, Issue 3, 14 July 2010, Pages 811-819, please follow the link.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Event Journal Club:Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice

Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice by Rhein et al.

Alex Bishop will be presenting the paper on Friday (6/11/2010) at Roskamp Institute.

Journal Club is held every Friday between 4 Pm-5pm. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Event: Journal Club

Benoit Mouzon will be presenting “Blood-brain barrier breakdown and repair by Src after thrombin-induced injury” by Liu et al.

The journal club will start at 4:00pm on Friday (may 28th 2010) in the auditorium at Roskamp Institute.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Announcement

The Roskamp Institute Memory Center and Clinical Trials Division is pleased to announce the addition of Ms. Yahdinah Alvarez to the clinical team.  Ms. Alvarez is an experienced clinical trial coordinator with expertise in Alzheimer’s and Parkinson’s disease studies.  If you or your loved one is suffering with Alzheimer’s disease or Parkinson’s disease, please contact the clinic at (941) 256-8018 for information regarding possible treatment options.

The Roskamp Institute Memory Clinic and Clinical Trials Division provide a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941) 256-8018.

News:Dr Crawford will be speaking at 2nd Annual Girls S.T.E.M. Summit

2nd Annual Science, Technology, Engineering & Math (S.T.E.M.) Summit at USF  Sarasota-Manatee on Saturday,  will start at 9 AM in May 22nd. Dr Crawford will give a speech about women in science.

For more information visit S.T.E.M. website.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Alzheimer’s beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2

By Patel NS, Mathura VS, Bachmeier C, Beaulieu-Abdelahad D, Laporte V, Weeks O, Mullan M, Paris D.

Published in J Neurochem. 2010 Jan;112(1):66-76. Roskamp Institute, Sarasota, Florida, USA. npatel@scripps.edu

Abstract

Beta-amyloid peptides (Abeta) are the major constituents of senile plaques and cerebrovascular deposits in the brains of Alzheimer’s disease patients. We have shown previously that soluble forms of Abeta are anti-angiogenic both in vitro and in vivo. However, the mechanism of the anti-angiogenic activity of Abeta peptides is unclear. In this study, we examined the effects of Abeta1-42 on vascular endothelial growth factor receptor 2 (VEGFR-2) signaling, which plays a key role in angiogenesis. Abeta inhibited VEGF-induced migration of endothelial cells, as well as VEGF-induced permeability of an in vitro model of the blood brain barrier. Consistently, exogenous VEGF dose-dependently antagonized the anti-angiogenic activity of Abeta in a capillary network assay. Abeta1-42 also blocked VEGF-induced tyrosine phosphorylation of VEGFR-2 in two types of primary endothelial cells, suggesting an antagonistic action of Abeta toward VEGFR-2 signaling in cells. Moreover, Abeta was able to directly interact with the extracellular domain of VEGFR-2 and to compete with the binding of VEGF to its receptor in a cell-free assay. Co-immunoprecipitation experiments confirmed that Abeta can bind VEGFR-2 both in vitro and in vivo. Altogether, our data suggest that Abeta acts as an antagonist of VEGFR-2 and provide a mechanism explaining the anti-angiogenic activity of Abeta peptides.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Tech Tips, #2: Making a homemade frit for fused silica columns

By our own MS guru Jon Reed

A Thermo Engineer once told me that “Nano-LC is not for the faint-of-heart.” A 0.5µl bubble in a 10-port valve can make a mess of an experiment.  Incomplete proteolytic digestions can clog up your brand new $600 column and render it useless.  A few centimeters of post-column dead volume can cause significant peak broadening despite the fact that you have a $50,000 LC system.  The list of problems goes on and on.   This causes more than its share of heartache, which leads to this simple truth:

If the favorite pastime of proteomics researchers is bragging to one another about their latest and snazziest technological acquisitions, then the second favorite pastime is whining about how they don’t work.

Still, as time progresses, people chip away at old problems and find out how to do things better, faster, cheaper.  So this week, I’ll leave you with one less thing to cry about and describe HOW TO MAKE A BETTER HOMEMADE FRIT FOR FUSED SILICA COLUMNS.

I had originally learned to make frits by dipping a piece of fused silica into 75% KASIL and 25% DMF, however these frits were lengthy, un-reproducible, and lead to high back pressure and inconsistent chromatography.  That technique sucks.  Sorry, stinks.  No… wait… it sucks.

A new and improved protocol was first shared with me by Jennifer Busby and Valerie Cavett from Scripps.  They’re very smart, and you should read some of their papers. Go on… log on to Pubmed and get to reading.

It’s an adaption of earlier work by Maiolica et al (Proteomics 2005, 5, 3847–3850), and takes a whopping 2 minutes, and $0.25 of reagents from start to finish.  Well, that doesn’t include the ½ hour drying time, but if you’re saving that kind of time and money for a superior product, don’t complain!

OK, here goes…

  1. Make a Kasil/formamide mix (75/25) and use approximately 2 µL to wet a glass microfiber filter (GC/F, Whatman).
  2. Gently push and twist the end of a fused silica capillary onto the wetted filter.
  3. Dry the frit for 5 minutes at approximately 37ºC or at room temperature for approximately 20 minutes before packing.  Note: times given for a 75 µm capillary; larger diameters may need longer to dry before packing.

Note: different column IDs may require a 2nd glass fiber plug (do not wet this one) to ensure you don’t blow the frit loose.  To do this, first push the end of the fused silica tubing into a dry piece of filter and core out what you need, then repeat this on the wetted section of filter.  You may want to try this using 2 wetted cores, but that may lead to increased back pressure.  The only way to know is to try it out.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Reduction of b-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer’s disease

By Daniel Paris*, Nowell J Ganey, Vincent Laporte, Nikunj S Patel, David Beaulieu-Abdelahad, Corbin Bachmeier, Amelia March, Ghania Ait-Ghezala, Michael J Mullan published in Journal of Neuroinflammation 2010, 7:17

Abstract

Background: Ab deposits represent a neuropathological hallmark of Alzheimer’s disease (AD). Both soluble and insoluble Ab species are considered to be responsible for initiating the pathological cascade that eventually leads to AD. Therefore, the identification of therapeutic approaches that can lower Ab production or accumulation remains a priority. NFkB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Ab. We therefore explored whether the known NFkB inhibitor celastrol could represent a suitable compound for decreasing Ab production and accumulation in vivo.

Methods: The effect of celastrol on amyloid precursor protein (APP) processing, Ab production and NFkB

activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Ab accumulation was tested in a transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw) by immunostaining and ELISAs. An acute treatment with celastrol was investigated by administering celastrol intraperitoneally at a dosage of 1 mg/Kg in 35 week-old Tg PS1/APPsw for 4 consecutive days. In addition, a chronic treatment (32 days) with celastrol was tested using a matrix-driven delivery pellet system implanted subcutaneously in 5 month-old Tg PS1/APPsw to ensure a continuous daily release of 2.5 mg/Kg of celastrol.

Results: In vitro, celastrol dose dependently prevented NFkB activation and inhibited BACE-1 expression. Celastrol potently inhibited Ab1-40 and Ab1-42 production by reducing the b-cleavage of APP, leading to decreased levels of APP-CTFb and APPsb. In vivo, celastrol appeared to reduce the levels of both soluble and insoluble Ab1-38, Ab1-40 and Ab1-42. In addition, a reduction in Ab plaque burden and microglial activation was observed in the brains of Tg PS1/APPsw following a chronic administration of celastrol.

Conclusions: Overall our data suggest that celastrol is a potent Ab lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFkB dependent mechanism. Additional work is required to determine whether chronic administration of celastrol can be safely achieved with cognitive benefits in a transgenic mouse model of AD.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Journal Club

Jeremy Frieling is presenting “Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid- oligomers” by Gandy et al.

Location: Roskamp Institute

Date: May 14th 2010

Time: 4:00PM

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

FREE MEMORY SCREENING-Sarasota FL

Are you or someone you know suffering from memory loss or forgetfulness?

Roskamp Institute is offering FREE MEMORY SCREENING for adults age 60 or older.

For an appointment call:               Roskamp Institute

941-256-8018 ext. 349


The Roskamp Institute Memory Clinic and Clinical Trials Division provide a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941) 256-8018.

Anti-Tumoral Activity of a Short Decapeptide Fragment of the Alzheimer’s Abeta Peptide

By Daniel Paris • Nikunj Patel • Nowell J. Ganey • Vincent Laporte • Amita Quadros • Michael J. Mullan

Int J Pept Res Ther (2010) 16:23–3.  DOI 10.1007/s10989-010-9198-8

Abstract: The inhibition of angiogenesis is regarded as a promising avenue for cancer treatment. Although some antiangiogenic compounds are in the process of development and testing, these often prove ineffective in vivo, therefore the search for new inhibitors is critical. We have recently identified a ten amino acid fragment of the Alzheimer Ab peptide that is anti-angiogenic both in vitro and in vivo. In the present study, we investigated the antitumoral potential of this decapeptide using human MCF-7 breast carcinoma xenografts in nude mice. We observed that this decapeptide was able to suppress MCF-7 tumor growth more potently than the antiestrogen tamoxifen. Inhibition of tumor vascularization as determined by PECAM-1 immunostaining and decreased tumor cell  proliferation as determined by Ki67 immunostaining were observed following treatment with the Ab fragment. In vitro, this peptide had no direct impact on MCF-7 tumor cell proliferation and survival suggesting that the inhibition of tumor growth and tumor cell proliferation observed in vivo is related to the antiangiogenic activity of the peptide. Taken together these data suggest that this short Ab derivative peptide may constitute a new antitumoral agent.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Roskamp Institute Poster Abstract from VA Reasearch Week

As I mentioned before, most of the PhD students and research assistants from our Institute participated in poster session  that was organized as a part of VA Research Week event series. Here you will find the abstract of our posters, enjoy :)

Development of the Barnes Maze as an Alternative to the Morris Water Maze Following TBI in Mice.

Scott Ferguson1,2, Benoit Mouzon1,2, John Phillips1, Vani Ganapapthi1, Alex Bishop1, Gogce Kayihan1,2, Venkatarajan Mathura1,2, Michael Mullan1,2 , Fiona Crawford1,2

1The Roskamp Institute, Sarasota, FL, USA; 2 James A Haley Veterans Administration, Tampa, FL, USA

Traumatic brain injury (TBI) is suffered by approximately 1.4 million people in the United States each year. TBI is the leading cause of death and disability in the most active population (under 45 years of age) in industrialized countries. Within the military, TBI is associated with 59% of blast-associated injuries seen at Walter Reed Army Medical Center, and between January 2003 and May 2005, 31% of all admissions to WRAMC had a brain injury. Apolipoprotein E (APOE) polymorphisms are known to impact the outcome after TBI, with the APOE4 allele (and concomitant ApoE4 expressed protein) associated with worse outcome than ApoE3 following TBI.   As part of our TBI research program we are exploring the molecular, neurobehavioral and neuropathological outcome after TBI in mouse models of injury, including APOE transgenic mice.

In order to evaluate differential outcomes of injury and its effects on motor skills and memory, we have optimized a series of neurobehavioral tests in mice.  The Rotarod test measures motor skill and learning via a programmable rotating bar.  Rotarod has shown the ability to distinguish between injured and uninjured mice, and has shown appropriate trends between differing levels of injury.  Morris water maze is a test of spatial memory and learning originally designed for rats but later adapted for mice.  APOE3 mice performed better than APOE4 mice in our Rotarod results, demonstrating an APOE genotype-dependent effect on motor function following TBI.  However, in the cognitive paradigm not only did we fail to detect any APOE genotype-dependent effects, we observed no significant differences in performance between injured and uninjured mice.  We therefore explored other cognitive paradigms for their ability to discriminate between injured and uninjured mice.

The Barnes maze is analogous to the Morris water maze in that it is also a test of spatial memory and learning, but because swimming is not involved it is associated with less stress than MWM typically induces in mice.  Others have shown that there is a strain-dependent effect on the ability of mice to learn the water maze task as well as the Barnes maze task.  Given that C57BL/6J mice are reported to perform better on the Barnes maze task, and this is the background strain utilized in our research, we optimized a paradigm of the Barnes maze for use in our TBI studies.  Our results show a statistically significant effect of injury on the spatial memory and learning of C57BL/6J wild type mice.  Future studies will re-examine the effect of APOE genotype on spatial memory following TBI using this test.

This research was funded by a Department of Defense award (W81XWH-07-1-0700) to Dr. Fiona Crawford and by the Roskamp Foundation

APP is Internalized After CD40 Ligation Which Increases Aβ Production

Ghania Ait-Ghezala, Jeremy Frieling, Myles Mullan, Claude-Henry Volmar, and Michael J. Mullan.

CD40, a member of the tumor necrosis factor receptor superfamily, and its cognate ligand CD40L are both elevated in the brains of Alzheimer’s disease (AD) patients compared to controls. We have shown that pharmacological or genetic interruption of CD40/CD40L interaction results in mitigation of AD-like pathology in vivo in transgenic AD mouse models, and in vitro. Recently, we showed that CD40L stimulation could increase Aβ levels, but the mechanism causing this phenomenon is not known. Here we show that CD40 ligation triggers internalization of APP and that internalization by endocytosis is associated with increased Aβ production. Furthermore, anthocyanins, which are known to impact trafficking to and from lipid rafts, impair the production of Aβ by CD40L stimulated CD40. However, anthocyanins have no effect on CD40L treatment of a neuroblastoma cell line over-expressing the C-99 APP fragment suggesting that CD40L internalization has no effect on γ-secretase. This finding is consistent with previous data suggesting that endocytosis increases BACE activity. In summary, these data suggest that a general mechanism of increased Aβ generation may be lipid raft mediated internalization of APP allowing increased BACE activity on its substrate.

Neurobehavioral profiles of two mouse models of Gulf War Illness

Laila Abdullah1, Alex Bishop1, John Phillips1, Benoit Mouzon1,2, Scott Ferguson1,2, Vani Ganapathi1, Myles Mullan1,2, Ghania Ait-Ghezala PhD1,2, Michael Mullan MD, PhD1,2 and Fiona Crawford PhD1,2

Affiliations: 1Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, 2James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL, 33612.

Background: Gulf War Illness (GWI) is a multisymptom condition associated with service in the 1990-1991 Persian Gulf War conflict and affects around 250,000 US veterans. It is largely attributed to combined exposure to pyridostigmine bromide (PB) and overuse of pesticides and insect repellants.  After nearly two decades, there is still no treatment for GWI and the underlying pathologic factors associated with the observed central nervous system (CNS)-based symptoms in veterans remain unclear.  Current GWI animal models do not demonstrate the full spectrum of neurobehavioral features reported to be associated with GWI, which makes it particularly difficult to explore the efficacy of possible therapeutic options.  Therefore, we tested two different treatment paradigms in order to establish a mouse model of GWI, which exhibits motor, cognitive and anxiety-related symptoms that are observed in veterans with this illness.  Methods: For model A, a previously established treatment paradigm was used which showed pathological changes suggestive of neurodegeneration, however extensive neurobehavioral profiling was not performed. Treated C57BL6 mice received oral administration of 1.3mg/kg of PB in water, dermal application of 0.13mg/kg of permethrin (PER) and 40 mg/kg of N-N-diethyl m-toluamide 2 (DEET) in 70% ethanol and 5 minutes of restrained stress daily for 28 days, whereas control mice received vehicle for the same duration.  For model B, a new treatment paradigm was developed where CD1 mice in the treatment group were administered 2mg/kg of PB and 200 mg/kg of PER via i.p. in DMSO daily for 10 days and the control group received DMSO only.  Following treatment, neurobehavioral profiles were examined using the Rotarod test to assess motor deficits, the Open Field test for anxiety-related changes and the Morris Water Maze test to assess spatial memory.  Results: In model A, treatment was associated with significant impairment in sensorimotor function and presence of anxiety-related behavior, but there was no deficit in spatial memory.  In model B, a delayed adverse effect of treatment was observed on the outcome measures of anxiety and spatial memory, but there was no evidence of sensorimotor impairment.  Conclusion: These findings suggest that combined exposure to PB and pesticides/insect repellents may lead to CNS-based effects in mice that mimic some of the clinical symptoms observed in veterans with GWI.  Additional studies are required to determine whether all three neurobehavioral features can be produced in one mouse model and whether these changes correlate with pathological features associated with neurodegeneration.

Acknowledgment: Funding for this research is provided by a Congressionally Directed Medical Research award (GW080094) to Dr. Fiona Crawford.

Proteomic identification of plasma TBI biomarkers

Benoit Mouzon1,2, Alex Bishop1, Gogce Kayihan1,2, Ben Katz1, Scott Ferguson1,2, Jon Reed1, Venkatarajan Mathura1, Michael Mullan1,2 and Fiona Crawford1,2

1Roskamp Institute, Sarasota, Florida

2James A. Haley Veterans’ Hospital, Tampa, Florida

Traumatic Brain Injury (TBI) is a major cause of mortality and morbidity in both military and civilian populations. The current lack of prognostic biomarkers for TBI confounds treatment and management of patients and is of increasing concern as the TBI population grows.  As part of our TBI research program we are generating brain and plasma proteomic profiles from APOE3 and APOE4 transgenic mice which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI.  In this study we used proteomic approaches to identify the changes in plasma protein profiles in APOE3 and APOE4 mice following severe TBI, in order to determine peripheral biomarkers associated with a poor outcome after TBI.

Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation – iTRAQ) we have identified proteins that are significantly modulated as a function of APOE genotype, injury and the interactive term of “genotype*injury”. Analysis of modulated plasma proteins revealed significant differences in proteomic response at 24 hours, 1 month and 3 months post injury across genotypes.  From these proteomic datasets we have identified 83 proteins at the 24 hour timepoint, 170 at 1 month and 129 at 3 months post TBI. For each timepoint, the identified proteins included those whose response was dependent on injury or the injury*genotype interaction, suggesting them as potential biomarkers of injury or outcome following injury.

In pilot validation studies, using antibody-based approaches in the original plasma from these mice, we have demonstrated the validity of our approach.  These preliminary data clearly demonstrate plasma protein changes that are not only injury-dependent but also interaction-dependent. The identified proteins include biomarkers that have been previously implicated in human TBI, and their time course and relationship to neurobehavior and pathology are now to be examined in these mouse models.  Importantly these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3 months time point, which is a considerable time post-injury in the mouse model and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury.  Furthermore, our identification of clusters of related proteins indicates disturbance of particular biological modules which increases their value beyond that of solitary biomarkers.  Clinical assays for many of these proteins are already established, which will facilitate translation of our findings from mouse to human.

The biomarker panels developed from this work will aid clinicians in the determination of diagnosis, prognosis, appropriate treatment and monitoring response to treatment, all of which are urgently needed in TBI management. The next step will be to investigate these potential biomarkers in human TBI patients and those studies will begin this year with the VA patient population and our clinical collaborators.

Acknowledgement:  This research was funded by a Department of Defense award (W81XWH-07-1-0700) to Dr. Fiona Crawford.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949


Handling Unstructured Data in Biological Research and Clinical Trials

Venkatarajan S. Mathura

Complex information that are available in a crude format make computational modeling and processing
a difficult objective in Biological and Health care research. Protocol revisions, process flexibility,
user adoptability should be considered in mind to develop an user friendly information management solution.
There is a great need to integrate data from several fields of research in a common platform to increase
process efficieny and reduce human errors. Realizing cost savings, application of knowledge mining tools on existing data and the need for data organization due to regulatory compliance, research groups and drug-discovery related industries are adopting electronic data capture and management solutions (EDC or EDM). Small scale setups still require an enterprise wide system that is both efficient, light weight, cost effective information management solutions that will be flexible to accomodate growth in the future. With the availability of field specific ontologies, controlled keywords/vocabularies, meta data management and language mapping tools, organization of unstructured data is becoming a feasible task. At the Roskamp Institute the Bioinformatics Group has developed several information management software to aid: Genomics, Proteomics, Animal Colony (Vivarium) and Clinical data management.

CliniProteus:
Clinical trials involve multi-site heterogeneous data generation with complex data input-formats and forms. The data should be captured and queried in an integrated fashion to facilitate further analysis. Electronic case-report forms (eCRF) are gaining popularity since it allows capture of clinical information in a rapid manner. We have designed and developed an XML based flexible clinical trials data management framework in .NET environment that can be used for efficient design and deployment of eCRFs to efficiently collate data and analyze information from multi-site clinical trials. The main components of our system include an XML form designer, a Patient registration eForm, reusable eForms, multiple-visit data capture and consolidated reports. A unique id is used for tracking the trial, site of occurrence, the patient and the year of recruitment.
Availability: http://www.rfdn.org/bioinfo/CTMS/ctms.html.

PWIMS 1.0: Proteomics Workflow and Information Management System

PWIMS is a software package that can systematically manage data in a proteomic laboratory setup. It is implemented in the LAMPP (Linux-Apache-MySQL-Perl/PHP) environment as a three-tier architecture. The client-tier is a web-browser that uses a thin-client HTTP to request resources and display responses to the user. The middle tier consists of an Apache web server, PHP scripting language, the Zend (PHP script) engine. The database tier uses MySQL RDBMS. Data Models and Entity-Relationships have been defined for handling data at various levels.

Some of the features of PWIMS are:

User Management: Multiple user settings, password authentication and access restriction depending on user role

Project Management: Project tracking, online availability of experiment status, experiment results, coordinators information, timeline and date records of the project.

Scheduling & Workflow Control: Tracks the workflow using unique codes for gels and target plates, controls workflow step-skipping and erroneous data entry, systematically schedules next step in the process, lists pending jobs

Data Capture: Form-based data entry, automatic mapping and transfer of large project files using FTP protocols, data can also be entered in a simple EXCEL sheet and uploaded

Data Integration & Analysis: Mass spec results are integrated to gels and projects. Protein hits can be filtered and exported for future reference or any other software, e.g., PDQuest. External links to UniProt, PUBMED, etc. are automatically provided

Data Mining & Presentation: Sequence motif search, functional keyword search and advanced queries can be specified. Results are made available for presentation and sharing.

GEMAT Genomics Experiment Management and Analysis Tool . GEMAT is an information management system designed as client-server tool for handling Affymetrix GeneChip information. It has builtin analytical tools for performing data mining and posting microarry data to endusers.

Roskamp Institute is participating in VA Research Week Activities

Veterans Affairs is celebrating 85th year in research this week (April 26-30, 2010). One of the events is a poster session where scientists will be presenting their most recent work. We are proud to say that most of our PhD students and research assistants will be in the auditorium of the James A Haley VA Hospital in Tampa, FL to present their posters tomorrow (April 29th 2010). For more information about the VA Research Week please visit this site.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949


Roskamp Institute-LECOM collaboration

Dr. Corbin Bachmeier of the Roskamp Institute is currently investigating the drug efflux transport interactions of various antidepressants in collaboration with Dr. Gary Levin of the Lake Erie College of Osteopathic Medicine (LECOM) in Bradenton, FL.  Dr. Bachmeier and Dr. Levin are co-investigators of a grant, provided by Wyeth Pharmaceuticals, which examines the interactions of two antidepressant medications currently on the market, venlafaxine (Effexor) and desvenlafaxine (Pristiq), with the drug efflux transport proteins P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).  Previous efforts by this group found that treatment with venlafaxine in caco-2 cells, a model of intestinal absorption, induced the mRNA expression levels for P-gp.  This work is reported in the scientific journal Human Psychopharmacology: Clinical and Experimental (Ehret et al., 2007).  Their existing research aims to expound upon these findings by not only examining the impact of treatment with venlafaxine and its metabolite, desvenlafaxine, on the expression of P-gp at the protein level, but also determine their effect on BCRP protein expression levels.  In addition to testing in the caco-2 cells, this research will also evaluate the impact of these drugs on transporter expression in brain endothelial cells, which constitute the blood-brain barrier (BBB).  This research will examine the potential for drug-drug interactions with these therapies and may influence the manner in which these drugs are currently prescribed.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

High serum Abeta and vascular risk factors in first-degree relatives of Alzheimer’s disease patients

Alzheimer’s disease is clinically characterized by progressive cognitive decline accompanied by the presence of amyloid plaques and neurofibrillary tangles in the brain of Alzheimer’s patients. A small protein fragment beta-amyloid (Abeta) with 42 amino acids is shown to deposit earlier in the disease process than the slightly shorter form (40 amino acid fragment).  Both species of this protein fragment are considered toxic to the brain and are shown to have an important role in causing Alzheimer’s disease.  Current research suggests that the disease process in Alzheimer’s begins long before the presence of palpable symptoms and widespread damage in the brain. Therefore, use of beta-amyloid seems promising in identification of individuals at-risk of developing Alzheimer’s disease.  Clinical studies have previously shown that blood and cerebrospinal fluid levels of Abeta may be helpful in diagnosis of Alzheimer’s disease but are influenced by factors such as presence of family history and other risk factors. The main objective of a recent study published by the scientists at the Roskamp Institute was to determine whether elevated blood Abeta levels among the first-degree relatives of patients with Alzheimer’s disease are associated with certain risk factors of cardiovascular disease that are also risk factors Alzheimer’s disease, such as hypertension.  Blood Abeta was measured in disease-free first-degree relatives of patients with Alzheimer-like dementia. Study participants were recruited as part of an ancillary study of the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT subpopulation) which was funded by the National Institutes of Health (UO1AG15477).  Examination of Abeta in this group of individuals showed that Abeta(1-40) fragment was positively associated with age and use of anti-hypertensive medications, but a negative relationship was observed in those individuals who experienced some increase in systolic blood pressure, despite being on anti-hypertensive medication.  On the other hand, the more toxic Abeta(1-42) was associated with statin use (medications used for lowering cholesterol) and with high-density lipoproteins was observed among statin nonusers. These findings suggest that high Abeta in blood samples of family history-enriched individuals may be due to enrichment of vascular risk factors and may reflect presymptomatic stage of Alzheimer’s disease.  As anti-hypertensive medications and statins are considered to be protective against Alzheimer’s disease onset, it remains to be determined whether their association with Abeta reflects mitigation of Abeta-related toxicity in the brain. Longitudinal evaluation of blood Abeta in this cohort will provide a better understanding of the significance of this association in Alzheimer’s disease etiology.

By Abdullah L, Luis C, Paris D, Ait-ghezala G, Mouzon B, Allen E, Parrish J, Mullan MA, Ferguson S, Wood M, Crawford F, Mullan M. These findings were published in Molecular Medicine 2009 Mar-Apr;15(3-4):95-100.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

Journal Club: The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia

JC Nowell Ganey will present “The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia” on Thursday (29th April 2010) at 4:00pm in Roskamp Institute. You can find the article in the following link.

The Roskamp Institute provides a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941)752-2949

Alzheimer’s Disease Anti-Inflammatory Prevention Trial

The Roskamp Institute Memory Center is actively following a large number of subjects who participated in the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT). Although earlier detection and the development of disease modifying treatment continues to be a primary focus of research and several potential compounds are under clinical trial, more prevention studies are needed.

The Roskamp Institute provides a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941) 256-8018.

Adaptation of the circular platform spatial memory task for mice: use in detecting cognitive impairment in the APPSW transgenic mouse model for Alzheimer’s disease

A methodology is described for use of a 16-hole circular platform task to test spatial memory in mice. Both bright light and a fan were used to motivate mice to escape the platform surface through a single hole containing an attached escape box. For each daily trial, three correlated measures (escape latency, number of errors, and error rating) comprehensively evaluated cognitive performance. In an initial study, the ‘spatial’ nature of this task was demonstrated by the much poorer performance of non-transgenic mice when visual cues are removed. Behavioral sensitivity of the circular platform task was then shown through its ability to discern cognitive impairment in 7-month-old transgenic mice, carrying the mutant APPSW gene for early-onset Alzheimer’s disease in humans, from non-transgenic litter-mates. Since there are currently only a few tasks available to definitively test cognitive performance in mice, the circular platform task offers a versatile, multiple-measure option with numerous advantages. Particularly in view of the increasing number of genetically manipulated mouse models being produced, the circular platform task should be most useful in providing a sensitive evaluation of cognition in mice.

Characteristics of thein VitroVasoactivity of β-Amyloid Peptides

Fiona Crawford1, Zhiming Suo, Chunhong Fang and Mike Mullan

Roskamp Laboratories, Department of Psychiatry, 3515 East Fletcher Avenue, University of South Florida, Tampa, Florida, 33613

Abstract

The β-amyloid (Aβ1–40) peptide has previously been shown to enhance phenylephrine contraction of aortic ringsin vitro.We have employed a novel observation, that Aβ peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of Aβ peptides, the role played by free radicals and calcium in the vasoactive mechanism, and the requirement of an intact endothelial layer for enhancement of vasoactivity. Rings of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made between post- and pretreatment contractions. In this system, vessel constriction is consistently dramatically enhanced by Aβ1–40, is enhanced less so by Aβ1–42, and is not enhanced by Aβ25–35. The endothelium isnotrequired for Aβ vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by Aβ peptides. In contrast to Aβ-induced cytotoxicity, Aβ-induced vasoactivity is immediate, occurs in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the Aβ peptides. We conclude that the mechanism of Aβ vasoactivity is distinct from that of Aβ cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endothelium suggests that loss of the free radical balance (between NO and O−2) may be a secondary influence on Aβ enhancement of vasoconstriction. These effects of Aβ on isolated vessels, and reported effects of Aβ in cells of the vasculature, suggest that Aβ-induced disruption of vascular tone may be a factor in the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. Although the mechanism of enhanced vasoconstriction is unknown, it is reasonable to propose thatin vivocontact of Aβ peptides with small cerebral vessels may increase their tendency to constrict and oppose their tendency to relax. The subclinical ischemia resulting from this would be expected to up-regulate βAPP production in and around the vasculature with further increase in Aβ formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete destruction of cerebral vessels and consequently neuronal degeneration in the affected areas.

Author Keywords: β-amyloid; vasoactivity; Alzheimer’s disease; cerebral amyloid angiopathy; endothelin-1.

Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer’s disease

Daniel Paris email, Nowell J Ganey email, Vincent Laporte email, Nikunj S Patel email, David Beaulieu-Abdelahad email, Corbin Bachmeier email, Amelia March email, Ghania Ait-Ghezala email and Michael J Mullan email

The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA

author email corresponding author email

Journal of Neuroinflammation 2010, 7:17doi:10.1186/1742-2094-7-17
Published: 8 March 2010
Abstract
Background

Aβ deposits represent a neuropathological hallmark of Alzheimer’s disease (AD). Both soluble and insoluble Aβ species are considered to be responsible for initiating the pathological cascade that eventually leads to AD. Therefore, the identification of therapeutic approaches that can lower Aβ production or accumulation remains a priority. NFκB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Aβ. We therefore explored whether the known NFκB inhibitor celastrol could represent a suitable compound for decreasing Aβ production and accumulation in vivo.
Methods

The effect of celastrol on amyloid precursor protein (APP) processing, Aβ production and NFκB activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Aβ accumulation was tested in a transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw) by immunostaining and ELISAs. An acute treatment with celastrol was investigated by administering celastrol intraperitoneally at a dosage of 1 mg/Kg in 35 week-old Tg PS1/APPsw for 4 consecutive days. In addition, a chronic treatment (32 days) with celastrol was tested using a matrix-driven delivery pellet system implanted subcutaneously in 5 month-old Tg PS1/APPsw to ensure a continuous daily release of 2.5 mg/Kg of celastrol.
Results

In vitro, celastrol dose dependently prevented NFκB activation and inhibited BACE-1 expression. Celastrol potently inhibited Aβ1-40 and Aβ1-42 production by reducing the β-cleavage of APP, leading to decreased levels of APP-CTFβ and APPsβ. In vivo, celastrol appeared to reduce the levels of both soluble and insoluble Aβ1-38, Aβ1-40 and Aβ1-42. In addition, a reduction in Aβ plaque burden and microglial activation was observed in the brains of Tg PS1/APPsw following a chronic administration of celastrol.
Conclusions

Overall our data suggest that celastrol is a potent Aβ lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFκB dependent mechanism. Additional work is required to determine whether chronic administration of celastrol can be safely achieved with cognitive benefits in a transgenic mouse model of AD.

Cross Validation of the Montreal Cognitive Assessment in Community Dwelling Older Adults Residing in the Southeastern US

By Cheryl A. Luis, Andrew Keegan, and Michael Mullan

Int J Geriatr Psychiatry. 2009 Feb;24(2):197-201.

Suitable methods of earlier detection of memory changes, before the full onset of a dementia are needed.  Methods such as imaging for abnormal protein accumulation in the brain and lumbar puncture to measure abnormal proteins in cerebral spinal fluid are not likely to be useful for wide-scale use due to costs and the invasive nature of the procedure.  In this study, we examined the utility of a brief cognitive screen (the Montreal Cognitive Assessment; MoCA), compared to a widely used instrument (the Mini-Mental State Exam; MMSE) in detecting older adults living in the community experiencing significant memory decline and the early signs of dementia. One hundred and eighteen individuals, over the age of 70, participated in the project. The MoCA proved to be highly sensitive in identifying participants with memory problems.  The MMSE was ineffective in comparison. Brief screening instruments such as the MoCA provide an objective and cost-effective means of determining the need for further evaluation of memory changes in older adults at risk for dementia.

The Roskamp Institute provides a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941) 256-8018.

Volunteers for early detection of cognitive decline in older adults

Dr. Cheryl Luis of the Roskamp Institute was awarded a New Investigator Research Grant from the Alzheimer’s Association in 2009.  She is studying the potential usefulness of a blood test in combination with a paper and pencil memory test for early detection of cognitive decline in older adults.  Additional research volunteers are needed.  If you or your loved one has been diagnosed with Alzheimer’s disease or Mild Cognitive Impairment and are interested in participating in a brief study, please call (941) 256-8018

The Roskamp Institute provides a full range of services for individuals with Alzheimer’s disease including diagnostic work-up and follow-up treatment, neuropsychological examination, clinical trial opportunities, and memory screening.  For more information, please call (941) 256-8018.

Roskamp Institute hosted a town hall meeting for the Alzheimer’s Association.

Sarasota, FL The Roskamp Institute hosted a town hall meeting for the Alzheimer’s Association. Presented was “A Reason to Hope”, an Alzheimer’s Services and Treatment Update. The meeting was well attended by caregivers and local community leaders. Dr. Cheryl Luis, Associate Clinical Director of the Roskamp Institute Memory Center, presented some of her current research to the attendees. Dr. Maria Carrillo, Director of Medical and Scientific Relations, from the National Alzheimer’s Association home office in Chicago, updated the audience about the latest developments in the fight against Alzheimer’s disease. While Gloria Smith, President & CEO of the Alzheimer’s Association – Florida Gulf Coast Chapter, presented the various services and the resources available to victims of the disease and their caregivers. The audience took part in a very encouraging question and answer session with Dr. Carrillo.

After the town hall meeting, Dr. Carrillo toured the Institute’s laboratories and had lunch with the Institutes scientific and clinical staff where they discussed current scientific research and developments in the Alzheimer’s field.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.
For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.

Roskamp Institute Scientist Awarded a grant from the Alzheimers Association to investigate a novel therapeutic agent for the treatment of Alzheimer’s Disease.

Sarasota, Fla. Dr. Daniel Paris, a senior scientist of the Roskamp Institute, was awarded an Investigator Initiated Research Grant Award from the Alzheimer’s Association to investigate the preclinical efficacy of a natural compound (celastrol) in a genetically engineered mouse model of Alzheimer’s disease.

The brain of Alzheimer’s disease patients is characterized by the accumulation of a small protein called beta-amyloid or Abeta and by the presence of intraneuronal tangle of a protein called tau. Abeta appears to be a key player in the pathology of Alzheimer’s disease and has been shown to trigger memory impairment, neuronal loss, abnormal tau protein accumulation, as well as cerebrovascular damages in various animal models of the disease. Abeta is produced by the cleavage of a larger protein precursor by two different enzymes called beta and gamma-secretase. Beta-secretase is the rate limiting enzyme in the production of Abeta and is viewed as a golden target for the treatment of Alzheimer’s disease. However despite intensive work, direct inhibitors of beta-secretase or Gamma-secretase with good drug-like properties have been extremely difficult to make. Given the difficulties being encountered by pharmaceutical industries for developing direct secretase inhibitors, Dr. Paris hypothesized that drugs which indirectly target the beta-secretase by affecting the production of the enzyme rather than by inhibiting it would be beneficial. Following the development of a screening method for identifying such drugs, Dr. Paris’ research team identified that a small molecule called celastrol is an indirect beta-secretase inhibitor that can potently oppose the production of Abeta. Celastrol is a natural compound extracted from a perennial creeping plant indigenous to a large area in southern China and known as the “Thunder of god vine”. Extracts containing celastrol have been given to Chinese patients for many years and are known to be efficient against inflammatory conditions. In the present research, Dr. Paris will determine whether celastrol holds promise as a therapeutic agent for the treatment of Alzheimer’s disease. He will further investigate whether this compound can prevent or reverse cognitive deficits, Abeta accumulation and tau pathology that affect a transgenic mouse model of Alzheimer’s disease.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.

Roskamp Institute Identifies New Class of Drugs to Treat Alzheimer’s Disease.

Sarasota, FL The Roskamp Institute today announced that its researchers have uncovered a new link between inflammation and Alzheimer’s disease and have identified a potential target for developing novel therapeutics for intervention in this disease. The study, led by Roskamp Institute’s Pancham Bakshi, Ph.D., is detailed in the American Chemical Society’s Chemical Biology Journal, a leading online publisher of peer-reviewed research.

It has long been known that Alzheimer’s disease is accompanied by inflammation, which both exacerbates and is caused by the underlying disease. In addition, it has long been suggested that abnormal deposits of a small protein, known as amyloid, which accumulate in the brain of those afflicted by Alzheimer’s disease, also trigger an inflammatory response. This inflammatory response is thought to be detrimental to nerve cells, eventually causing their destruction.

Recent research at the Roskamp Institute has revealed that inflammation can lead to the production of more amyloid, and researchers have found that a specific receptor on the nerve cell surface, known as CXCR2, is an interface between inflammation and new amyloid production. As specific inflammatory molecules contact CXCR2, a signal is generated which results in increased amyloid production. The presence of the abnormally occurring amyloid; therefore, contributes to its own reproduction through the inflammatory response it triggers.

“I found that by genetically knocking out CXCR2, we can reduce the amount of amyloid in various laboratory models and, by using drugs that specifically block the CXCR2 receptor, we are able to show that a decrease in production of amyloid can be achieved,” said Dr. Bakshi. “This study, which for the first time shows the early role of inflammation in AD, opens a new door for therapeutic intervention, potentially leading to the use of CXCR2 blocking agents as a way to treat both the inflammation and the amyloid production in Alzheimer’s disease.”

“Finding new classes of medications for Alzheimer’s disease is a world-wide priority,” said Michael Mullan, M.B.B.S., Ph.D., director of the Roskamp Institute. “Dr. Bakshi’s work highlights a new class of drugs that should have the benefit of both stopping inflammation and, importantly, stopping the accumulation of the pathologic amyloid. In addition to the drug Dr. Bakshi has already tested, she is making her own drugs to attack this potentially important target.”

Dr. Bakshi is currently a scientist II in the Roskamp Institute and leads the Laboratory of Chemical Biology and Drug Discovery in Neurology. Prior to the Roskamp Institute, Dr. Bakshi was a postdoctoral researcher with Dr. Michael Wolfe at Harvard Medical School, Center for Neurology from 2001-2004 and a sabbatical postdoctoral fellow at Harvard Medical School, Laboratory of Drug Discovery in Neurology with Dr. Michael Wolfe and Dr. Ross Stein from 2002-2003. Dr. Bakshi has a Ph.D. in Bioorganic Chemistry from the Center for Biochemical Technology, New Delhi, and a Master of Science in Organic Chemistry and Bachelor of Science in Chemistry from the University of Delhi, New Delhi.

The Roskamp Institute is a not-for-profit research Institute located in Manatee County and Hillsborough County, Florida, that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders and addictions with an emphasis on Alzheimer’s disease. The Roskamp Institute’s Memory Centers also offer comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.

Roskamp Institute Announces Enrollment of First Students to Participate in its Innovative Research Doctorate Program

Sarasota, FL Sarasota’s Roskamp Institute (Roskamp) today announced the first enrollment of students in its pioneering three-year Ph.D. program through which students will conduct full-time laboratory research with direct mentoring from internationally-recognized scientists. Roskamp is an Affiliated Research Centre (ARC) of the United Kingdom’s Open University (OU) and was recently granted a license from the Commission for Independent Education within the Florida Department of Education to begin this program.

“Roskamp has always played a significant role in training and mentoring top quality students, and we are delighted to now have a formal degree-awarding program,” said Dr. Fiona Crawford, associate director of Roskamp. “With the enrollment of our first successful applicants, we look forward to further enhancing the Institute and its many partners and collaborators in Florida, as well as the local developing biotechnology community.”

“Our Ph.D. program brings the opportunity for postgraduate research students to participate in a one-of-a-kind program that will expose them to a world-class research facility,” said Dr. Michael Mullan, director of Roskamp. “They will work side-by-side with exceptional scientists, perform hands-on, laboratory-based research and gain the practical knowledge necessary to succeed in their area of research, and emerge as fully operational professionals.”

The Institute has enrolled three students in its Ph.D. program, which will expose them to Roskamp’s state-of-the-art technology and will allow them to gain knowledge of the Institute’s key divisions, including chemistry, proteomics and molecular biology. The first class of students in the program will pursue dissertation research on Gulf War Syndrome, Traumatic Brain Injury and Alzheimer’s disease.

Laila Abdullah, M.S., is a graduate of the University of South Florida with a Bachelor of Science in Biology and a master’s in Epidemiology. Abdullah is studying the biological cause of the chronic and complex health problems that Persian Gulf War veterans experience compared to other veterans, using both standard molecular biology and advanced proteomic technology.

Scott Ferguson is a graduate of the University of Central Florida with a Bachelor of Science in Micro/Molecular Biology. Ferguson is studying how brain proteins respond to traumatic injury in order to identify new ways to treat the long-term consequences of these injuries which are of such high prevalence in the military and civilian populations.

Nowell Ganey, who is a graduate of the University of Florida with a Bachelor of Science in Nutritional Science, is building on the seminal work of lead Institute scientists by exploring the mechanisms linking vascular factors to the development of Alzheimer’s disease.

OU has a 110 acre campus in Milton Keynes, England, and is also a distance learning university and the leading eLearning University in the U.K. for its quality of teaching. With the addition of Roskamp, there are 24 OU ARCs around the world. In addition to the research degree programs, OU is a very large teaching university. More than 2 million students have studied at OU since its inception in 1971. The OU is accredited by the U.S. Middle States Commission on Higher Education.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.

Southeast High School’s Roskamp Institute project placed first in Florida and fifth in National Technology Students Association finals

Sarasota, FL Roskamp Institute was the focus of Southeast High Technology Student Association (TSA) team project in the Medical Technology category which was awarded fifth place in the Nation at the 31ST Annual TSA National Conference in Denver, Colorado June 28 – July 2 after wining first place in the State of Florida competition held in Orlando on March 3rd 2009 . The team fromSoutheast attended the National finals representing the State of Florida and holds the distinction of being Florida’s Most Outstanding TSA High School.

The Team’s project highlighted some of the cutting edge research being carried out at the Roskamp Institute. The TSA team members from Southeast High are Maya Meredith, Andres Romero, Rachel Metras, Lor Gregor, Diego Corzo, John Nguyen, Marissa Bressi. As well, the team won first place in Florida for another Roskamp-assisted project in the Scientific Visualization category. Southeast High School is located in Bradenton, Florida and is an International Baccalaureate Diploma School.

Please click here to see video of this award wining work by the Team from Southeast High.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.
Videos

Local Researchers at Roskamp Institute to Test Investigational Gammaglobulin Treatment for Alzheimer’s Disease

This summer, researchers from Roskamp Institute in Sarasota, FL, will begin testing an investigational approach to slowing down the progression of Alzheimer’s disease (AD) using Intravenous Immune Globulin (IGIV), also known as gammaglobulin. IGIV is currently used to treat primary immunodeficiency disorders but is not currently approved for treating AD, which is one of the leading causes of dementia in the elderly.

Initial research in experimental models and patients suggests that immunotherapy targeting beta amyloid (the protein that forms the core of plaques in the brain) may provide an effective way to treat AD. Antibodies that bind to beta amyloid are present in IGIV, which is made from the blood of several thousand healthy adults. This effort seeks the public’s participation in testing IGIV in a major clinical trial that is jointly funded by the National Institute on Aging and Baxter International Inc.

One of the hallmarks of AD pathology is an abundance of beta-amyloid deposits in the brain. While it is not yet known if beta amyloid plaques cause AD or are a byproduct of the disease, scientists are interested in finding ways to reduce the toxic effects of beta amyloid on the brain. Antibodies against beta amyloid may do so by binding to toxic forms of beta amyloid, thereby neutralizing them and/or promoting their elimination.

“We are investigating whether IGIV, which contains naturally occurring human anti-amyloid antibodies, will defend the brain of AD patients against the damaging effects of beta amyloid. If it does, giving IGIV to patients with mild to moderate Alzheimer’s may potentially slow the rate of progression of the disease,” says Dr. Andrew Keegan, the principal investigator for the study at Roskamp Institute.

“In our initial studies in AD patients, IGIV provided cognitive benefits, improved brain metabolism and reduced beta amyloid levels in the spinal fluid,” says Norman Relkin, M.D., Project Director and Director of the Weill Cornell Alzheimer’s Disease and Memory Disorders Program. In a Phase II trial at Weill Cornell, Dr. Relkin reported that participants undergoing several months of continuous IGIV therapy also demonstrated improvement in their activities of daily living. He added, “These findings, as well as IGIV’s established record of use for treating other diseases, provide a strong rationale for further study in AD patients on a larger scale.”

The GAP (Gammaglobulin Alzheimer’s Partnership) Study will examine the safety, effectiveness and tolerability of IGIV in patients with mild to moderate AD. GAP is recruiting 360 participants at 36 sites nationwide. This large Phase III clinical trial expands on earlier testing, is one of two Phase III trials, and is part of the final phase in studying IGIV as a potential treatment for AD before seeking regulatory approval.

The GAP trial is a double-blind, placebo-controlled study in which two-thirds of participants will receive IGIV and one-third will receive placebo. It will last up to 82 weeks. Sites are looking for study volunteers who fit the following criteria:

* Male or female, 50-89 years old
* Have been diagnosed with probable mild to moderate Alzheimer’s disease
* Have a study partner (spouse, child, sibling or friend) in contact with the participant 10 hours/week or more

The trial is being conducted by the Alzheimer’s Disease Cooperative Study (ADCS), a nationwide consortium of research centers and clinics coordinated by the University of California at San Diego and directed by Paul Aisen, M.D.

“As many as five million Americans may be afflicted now and with the numbers growing rapidly, ADCS clinical trials such as the GAP study are essential to finding new and more effective treatments for Alzheimer’s disease,” Aisen commented.

The ADCS is primarily supported by the National Institute on Aging (NIA), part of the National Institutes of Health. The GAP study is jointly funded by Baxter International Inc. and the NIA. For further information on the trial, please go to: http://www.adcs.org/Studies/IGIV.aspx

For more information on this study and Alzheimer’s disease, please visit the Alzheimer’s Disease Education and Referral Center website: http://www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=282

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

Contact:
Dr. Andrew Keegan Jeffree Itrich
Roskamp Institute Alzheimer’s Disease Cooperative Study
email: rclinic @ rfdn.org email:jitrich @ ucsd.edu
Phone: (941)256-8018 Phone:(858)622-5827
www.mullanalzheimer.com www.adcs.org

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.

World Alzheimer’s Day: Leaders Call for Early Diagnosis and Aggressive Research

Alzheimer’s disease carries an annual price tag of $148 billion dollars, not to mention the personal toll that it takes on the over 5.3 million patients and their families.

More than 5.3 million Americans are living with Alzheimer’s, and every 72 seconds someone in America develops the disease. According to the Alzheimer’s Association, by mid-century someone will develop Alzheimer’s every 33 seconds, and there will be nearly a million new cases per year.

“With the country facing unprecedented economic challenges and a rapidly aging baby boomer population, now is the time to address the burgeoning Alzheimer’s crisis that triples healthcare costs for Americans aged 65 and over,” said Harry Johns, Alzheimer’s Association CEO.

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive loss of memory and cognitive function. It destroys brain cells, causing problems with memory, thinking, and behavior that are severe enough to affect everyday life.

Experts believe that early detection of Alzheimer’s disease and early intervention with improved therapies provides the greatest opportunity to modify or halt disease progression. Most current therapies for Alzheimer’s treat the symptoms associated with it and not the disease itself.

“There is a rich, diverse variety of treatment possibilities for Alzheimer’s that scientists are exploring, offering great hope that drugs that may slow or even reverse disease progression could be on the horizon—saving millions of dollars in public health programs,” said Ronald Petersen, M.D., Ph.D, Alzheimer’s Association Medical Scientific Advisory Council Chair. On World Alzheimer’s Day, we renew our commitment to early diagnosis and aggressive Alzheimer’s research in order to improve the health outcomes for people living with this disease.

Dr. Andrew Keegan and other local physicians are currently researching potential new treatments for Alzheimer’s patients that target causes of the disease, such as amyloid plaques in the brain. The buildup of these plaques is thought to cause Alzheimer’s disease. Some of these investigational drugs use antibodies, or immune system proteins, to dissolve the plaques.

“There are too many lives, too little time, and too much at stake for anything less than an aggressive plan to address the threat of this disease,” Johns said.

Roskamp is a not-for-profit research Institute located in Sarasota, Fla., that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinic also offers comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete.

Contact:
Dr. Andrew Keegan
Roskamp Institute
email: rclinic @ rfdn.org
Phone: (941)256-8018
www.mullanalzheimer.com

For more information, please contact the Institute at (941) 752-2949, Roskamp’s Clinical Trials Division in Sarasota at (941) 256-8018 or visit www.mullanalzheimer.com.

Dementia in Older Women

A recent paper published in the Journal Neurology, which analyzed over 900 people, suggests that almost half of all women in their nineties are suffering from dementia. The study carried out in California is one of a few looking specifically at the rates of dementia in the very old. However, given our increased life expectancies, the over ninety group is growing rapidly in many populations, including that of the United States. Importantly, there seems to be a sex difference in the risk for Alzheimer’s or dementia in general over the age of ninety.

In men, for instance, although there was an increase in the likelihood of having dementia over the age of ninety, it did not increase as much as it did in women. In women, the likelihood of having dementia doubled every five years after the age of ninety. Previous studies have suggested that the risk for dementia is higher in women than it is in men. But other studies have disputed this. This present study seems to confirm that the risk for women is greater than men, at least after the age of ninety years.

Therefore, if you divide dementia populations by sex over the age of ninety, about 45% of women will have dementia compared to 28% of men. Importantly the study also suggested that women who had used their brains (intellect) more throughout life and had achieved higher education, were much less likely to develop dementia than those who had not.

Understanding why women in this age group might be at higher risk will take additional studies. But it is known, for instance, that women are more likely than men to develop stroke and heart disease as they age. Both of these are independent risk factors for dementia and exacerbate Alzheimer’s symptoms.

Researchers at the Roskamp Institute are interested in finding new treatments for Alzheimer’s disease and clues from sex differences that confer different risks for Alzheimer’s are important because they may point to more treatment strategies.

Researchers have, for instance, speculated that estrogen is a protective factor for Alzheimer’s disease, but proactive treatment with estrogen has not been shown to be preventative in clinical trials. In the present study, the idea that vascular risk factors (which are more prevalent in women as they age) are contributory to Alzheimer’s is consistent with much of the work of Roskamp Institute scientists showing that in the presence of amyloid, damage to the vasculature is heightened and the consequences of vascular damage has greater impact on the brain in the presence of early Alzheimer’s disease than in normal individuals. These and other clues are leading Roskamp Institute scientists towards new treatments for the disease, some of which should be entering clinical trials in 2008.

Alzheimer’s and Blood Pressure

The relationship between blood pressure and Alzheimer’s disease is complex. However, we do know that blood pressure raised in mid-life (hypertension) is a risk for the development of Alzheimer’s disease later on. Uncontrolled hypertension is a risk for dementia in general. In fact, stroke related dementias are primarily caused by either clotting or small bleeds in the brain. Hypertension can lead to bleeding, primarily in the brain, but can also damage the heart triggering the release of small clots that lodge in the brain, thus depriving the nerve cells (neurons) of oxygen supply.

It remains unclear to scientists why hypertension is a risk for Alzheimer’s disease, but we do know that in spontaneously hypertensive rats, there is a tendency to accumulate some of the pathology of Alzheimer’s disease.

In 1996, researchers at the Roskamp Institute discovered that the causative protein in Alzheimer’s (the amyloid protein) has a drastic effect on blood vessels. The effect is to increase the propensity of blood vessels to constrict. Subsequently, others show that after a small stroke (when blood vessels close down temporarily) the presence of amyloid tends to keep the blood vessels closed. It is assumed that the consequence of reduced blood flow to the brain, secondary to closed blood vessels, causes deprivation of oxygen and glucose to the neurons, thus causing more damage in a brain with high amyloid levels than one with not.

Translated into clinical terms, this means that the effect of a small stroke on somebody who is in the early stages of Alzheimer’s can be more devastating than somebody who is not. In fact, a study of nuns who were asked to complete mental state questionnaires in life and who subsequently died has revealed an important interaction between small strokes and the clinical signs of Alzheimer’s. Even though some nuns had amyloid deposits in their brain, they did not exhibit the symptoms of amyloid in life. Those nuns that had amyloid deposits but did exhibit the clinical symptoms of Alzheimer’s in life also had multiple small strokes.

Thus, damage to the blood vessels in the presence of amyloid is more devastating than if amyloid is absent. Hypertension tends to damage blood vessels throughout the body, but it is only in the brain that amyloid accumulates and can contribute to poor recovery after vascular injury.

What does this mean for patients treated at the Roskamp Institute? Patients are advised to take particular care to have their blood pressure and cardiovascular status monitored. High lipid or triglyceride levels can contribute to cerebrovascular (brain/blood vessel) damage and uncontrolled or poorly monitored high hypertension can also be highly detrimental. In addition, we know that other cardiac problems, such as arrhythmias can contribute to cerebrovascular damage, as mentioned, by throwing off small clots.

As we await effective treatments to combat Alzheimer’s directly, we need to ensure that we control other disorders which can contribute significantly to rapid declines in mental status. Interestingly, some antihypertensives seem to be able to control the risk for Alzheimer’s disease as well as controlling blood pressure.

Researchers at the Roskamp Institute have clearly shown that this does not apply to all antihypertensives and they are investigating why some are able to regulate both blood pressure and can reduce the incidence of Alzheimer’s disease while others cannot. This is an important area of research and clearly one that holds out hope for Alzheimer’s sufferers as the search for new treatments continues.

What do the names of Barack Obama, Hillary Clinton, and John McCain have to do with Alzheimer’s disease?

Alzheimer’s disease is a neurodegenerative disorder (i.e., one which attacks neurons in the brain) which robs us of our memories, language, reasoning and thought. However, the clinical picture of Alzheimer’s has a very distinctive pattern which distinguishes it from other forms of dementia (dementia is a general term which simply means the loss of memory, some other mental function, and the loss of normal social functioning). In Alzheimer’s disease, the early signs are almost invariably the same and include loss of memory for recently presented information.

What does this mean practically? It means that someone in the early stages of Alzheimer’s will not remember information presented to them a short time ago. For instance, if somebody receives a phone call, a few minutes later they may not remember who it was who called. Similarly, if they set out for the grocery store, once they arrive there they may not remember what it is they set out for.

Today, we are so used to receiving news all the time from our computers, our televisions, radios, and mobile phones that we don’t realize that we are being presented with new information all the time. The Alzheimer’s sufferer is at a particularly grave disadvantage in this situation. Current events may escape their memory stores and a good test of whether someone may be suffering from the disorder or not is whether they can remember information that appears as news on television or other ways. So, for instance, knowing the big events in the campaign for the US presidential election will be registered by most of us and remembered. The Alzheimer’s sufferer may not know that Hillary Clinton has dropped out of the race nor that Barack Obama has been nominated. Knowledge of these events, which most of us take for granted are lost to the Alzheimer’s sufferer and thus monitoring our loved ones and friends for signs that they are not aware of current events may help us to detect early signs of the disease. Concern that somebody may not be acquiring new information should be a trigger to have them evaluated in a memory disorder clinic.

The Roskamp Institute has two such clinics – one in Tampa and one in Sarasota, Florida and they offer full evaluations for Alzheimer’s and other causes of memory loss.

Double Amyloid Causes Memory Loss

A recent paper (June 22nd from scientists from Harvard University and Trinity College, Dublin) has shown that the amyloid protein is most toxic to memory when it appears in a double form. The researchers extracted the amyloid protein (the small protein that has long thought to be the cause of Alzheimer’s) from the brains of Alzheimer’s disease victims and when the proteins were injected into rats, they noted that, depending on the specific form of amyloid, memory impairment occurred.

Alzheimer, himself, saw the accumulation of amyloid protein in what are now know as plaques, but these accumulations of amyloid represent many, many single amyloid molecules aggregated together.

The researchers found that this highly aggregated form of amyloid was not injurious to memory. However, when the amyloid protein occurred in just a doublet, (i.e., two molecules of amyloid stuck together) then it was in its most toxic form. Single amyloid (which we all produce for much of the time) was harmless to memory. These findings are important because the doublet form of amyloid is soluble and therefore can travel freely throughout the brain. These findings also suggest that the aggregated form that is visible to the eye under the microscope is not the most important form for researchers to prevent.

These findings are of particular interest to researchers at the Roskamp Institute, who showed in 1996 that soluble forms of amyloid could be toxic to blood vessels, increasing the likelihood that they would constrict. This is a particularly bad thing, especially after stroke, and it raised the possibility at that time that the soluble forms of Aß of amyloid might be more important than the aggregated forms.

These new findings also suggest that treatments aimed at lowering the amount of the amyloid doublet, might be those that are most effective in the disease. The new vaccine treatment, for instance, aimed at lowering the amount of amyloid by soaking up the amyloid with an antibody, might be effective at lowering these amyloid doublets. Other drugs that are coming on-line for the treatment of Alzheimer’s also targeted at the amyloid protein will now, no doubt, be examined to see whether they can lower the amount of the amyloid doublet.

Researchers at the Roskamp Institute are dedicated to finding new treatments and cures for Alzheimer’s disease. They were among the first in the world to show that the amyloid protein was most likely central to the disease process. This theory is now being tested in clinical studies throughout the world with exciting recent results suggesting that, indeed, the removal of amyloid might be an effective treatment for the disease (see recent reports on Elan Pharmaceuticals).

First Critical Clinical Tests of the Amyloid Theory of Alzheimer’s Disease

In 1991, researchers currently at the Roskamp Institute published a paper in the highly prestigious Nature journal entitled “Early Onset Alzheimer’s Disease Caused by Mutations of the Amyloid Gene”. This and related findings were historic milestones in the understanding of the causes of Alzheimer’s disease. Today, seventeen years later, Roskamp Institute researchers are delighted to hear that Elan, one of the largest pharmaceutical companies, is having success with an approach which targets the amyloid protein.

The early findings by Roskamp researchers placed amyloid at center stage as the cause of the disease. Now Elan’s vaccine, which is targeted to soak up the amyloid protein, may be a verification that reducing amyloid accumulation is a way to tackle the disease. Although some researchers remain skeptical of the validity of this approach, the early results from Elan’s Phase II study, published this week (June 17) indicate that reducing amyloid levels with the anti-amyloid vaccine has slowed the rate of progression of the disease in some patients. Interestingly, the vaccine approach has been helpful in cases of the disease that do not have a high genetic risk loading. Although there was a hint that all cases of Alzheimer’s (even those with high genetic loading might benefit from the vaccine), there was not a statistically significant difference between placebo group and those individuals that carry an APOE4 gene. This gene is known to increase the likelihood of developing Alzheimer’s early in life and may represent a particularly aggressive form of the disorder. Nevertheless, the fact that there were trends in a treatment improvement in the high risk group and statistically significant improvement in income in the low genetic risk group, strongly suggest that targeting amyloid will be a therapeutically useful strategy.

For Roskamp Institute researchers the new data from Elan is very important as Roskamp Institute researchers have developed drugs that do the same thing as the vaccine, i.e., lower the accumulation of amyloid levels. One of those drugs is in clinical trials already in Europe and trials are set to begin in the US pending FDA approval.

For Alzheimer’s sufferers and Alzhiemer’s researchers alike, the news from Elan is very hopeful.

Elan Vaccine and Alzheimer’s Disease Drug development

The Roskamp Institute has a commitment to bring state-of-the-art new therapies to our patients at both the Sarasota and Tampa sites. For Alzheimer’s disease, for instance, the Institute is taking part in the Elan Wyeth clinical trials of a vaccine for Alzheimer’s disease. Important results for the Elan Wyeth vaccine were released on June 17, 2008.

The study of the vaccine called bapineuzumab (AAB-001) in a Phase II clinical trial was conducted in mild to moderate Alzheimer’s disease. The clinical trial lasted eighteen months and overall the bapineuzumab appeared to have clinical activity in treating the disease.

The company found that although the study did not attain statistical significance on the primary efficacy endpoints in the total study population, it was shown that in Alzheimer’s patients who do not carry the APO lipo protein E4 (APOE4) version of the APOE gene there were statistically significant and clinically meaningful benefits associated with the vaccine. The endpoints used included the Alzheimer’s disease assessment scale (ADAScog), the neuropsychological test battery (NTB), the mini-mental state examination (MMSE) and the clinical dementia rating scale (CDR). Interestingly too, when the company looked at brain scans of Alzheimer’s patients in the trial, they found that the MRI indication of loss of brain substance was decreased in those patients that were treated versus the placebo group.

The Roskamp Institute (Institute) is engaged in a Phase III study of the vaccine for Elan Wyeth and these encouraging results suggest that the larger clinical trial may also be beneficial. The vaccine targets are a small protein called amyloid, which researchers at the Institute believe is associated and triggers the disease pathology.

In fact, researchers at the Institute were among the first in the world to show that an accumulation of amyloid could cause Alzheimer’s disease. This they did by working with early-onset families (where the disease occurs in the 40, 50, or 60 year age groups) and showing that genetic errors in the amyloid gene were all that was responsible for the early build-up of the amyloid protein in the brain.

The Elan Wyeth vaccine is engineered to identify amyloid and remove it from the body and as such, holds potential for halting the disease progression. It is expected that the vaccine would be given every few weeks throughout the life of the Alzheimer’s sufferer.

This and other innovative treatments are available to our clinic population at the Roskamp Institute.

Alzheimer’s Disease Drug development

An article in the Wall Street Journal on the 18th of June 2008, encapsulates the current expectation, hope and knowledge in the field of Alzheimer’s disease research. Researchers at the Roskamp Institute (Institute) have been part of the history of the discovery of new possibilities for stopping this devastating disease.

The article importantly discusses the recent work of Elan and Wyeth and their vaccine approach to Alzheimer’s disease. The reason this is central to the work of the Institute is that the same target of the vaccine is the protein that was highlighted by Institute researchers in the early 1990s as being causal in the disease process. The protein called amyloid accumulates in the brains of those with Alzhiemer’s disease and early genetic studies by members of the Institute team showed that amyloid definitely could cause the disease in certain individuals. Articles published in Nature in the early 1990s verified the causal relationship between the buildup of amyloid and the development of Alzheimer’s disease.

Now, almost twenty years later, Elan and Wyeth have developed a vaccine called bapineuzumab, which targets amyloid and reduces its accumulation in the brain. Although the exact mechanism of the antibody vaccine is not known, it is believed to act as a sponge in the blood supply, sucking amyloid from the brain and disposing of it harmlessly around the body.

Interestingly, the Wall Street Journal article points out that although the vaccine Phase II study failed on some of its clinical endpoints, there was enough of a positive signal in the data to enthuse not only Wall Street but researchers world-wide that the lowering of amyloid may be an effective approach to stopping this devastating disease. Many drug companies world-wide are pursuing treatments for Alzheimer’s which lower amyloid. The Institute is one such not-for-profit group which has developed drugs which lower amyloid levels and which are now in clinical trials around the world.

It is estimated that the pharmaceutical industry and biotech companies will spend more than a billion dollars this year researching into new treatments for Alzheimer’s. A Phase III study for the vaccine is underway and is being conducted at clinical sites around the country, including the Roskamp Institute site in Sarasota, Florida. The Institute researchers and clinicians are gratified, not only that they contributed to the early understanding of the causes of Alzheimer’s disease, but that drugs now are coming into clinical trials that target amyloid and look as if they may well be effective in stopping this dreadful disorder.

Another very interesting aspect of the Phase II results from Elan and Wyeth, is that the vaccine seemed to have more benefit in some genetically non-predisposed individuals than others. A gene known as the APOE gene dictates our risk for Alzheimer’s disease, particularly regarding whether we are likely to get the disease when we are 65, 75, or 85. Two copies of the E4 version of APOE, for instance, increase the risk of getting the disease earlier in life. The Elan and Wyeth vaccine looks as if it wasn’t particularly effective in that group, although the numbers treated that were E4 carriers was quite small, as it is in the general population. However, for those not at high genetic risk, the results were significant in that, after eighteen months, there was statistically valuable reduction in the rate of decline of cognitive processes. Integrating genetic tests into clinical trials for Alzheimer’s disease has now become a standard and is one of the adjunct research tests conducted at the Institute.

Clinical research for Alzheimer’s Disease at the Roskamp Institute

Clinicians at the Roskamp Institute are conducting a clinical trial for Elan Pharmaceuticals, Inc. of San Francisco and Transition Therapeutics, Inc. of Toronto, Canada.

The drug is designated ELND005 and the study is a phase two study in mild to moderate Alzheimer’s disease. ELND005 is an orally available drug that is designed to prevent the aggregation of the amyloid peptide. The amyloid peptide is thought to be central to the disease process in Alzheimer’s disease.

As the amyloid peptide accumulates in the brain in Alzheimer’s disease patients, it forms aggregates which are toxic to neurons. ELND005, which was formally known as AZD103, was developed in collaboration with transition therapeutics and has been shown to be able to reduce the amount of amyloid that accumulates in the brains of transgenic mouse models of the disease. This reduction in accumulation correlates with improved memory testing in such animals.

Phase I studies have already been completed in healthy volunteers with ELND005. The drug is shown to be well tolerated and crosses the blood/brain barrier. Importantly, ELND005 has been shown to reach CSF concentrations in humans that are equivalent to the effective mouse concentrations that can reduce the burden of amyloid in mice.

The Phase II study design includes three treatment arms and one placebo group. The treatment arms receive twice a day oral dosing of ELND005. The dose is either 250 mg, 1000 mg, or 2000 mg. The treatment phase will last for 78 weeks.

The endpoints of the study will include cognitive and functional testing of mild to moderate Alzheimer’s disease patients and MRI imaging of brain volumes. Quality of life measures will also be included. As in all Phase II studies, safety will be a primary measure throughout the clinical trial.

Clinical researchers at the Roskamp Institute are committed to bringing new drug treatments like ELND005 to our Alzheimer’s population. It is hoped that either this drug or others like it will play a significant role in the control of Alzheimer’s disease in the near future.

The Roskamp Institute is developing its own drug therapies for Alzheimer’s disease. One of which, nilvadipine, is currently under clinical trials in Ireland. This drug is shortly to be brought into clinical trials in the United States pending FDA approval.

DRUG ADDICTION RESEARCH AT THE ROSKAMP INSTITUTE

The Roskamp Institute (Institute) is engaged in the study of drug addiction from a genomic and proteomic perspective.

The genomic analysis, which covers the examination of all the genes in the human genetic make-up allows research at the Institute to determine which genes respond in relation to exposure to certain drugs of addiction.

The proteomic analysis allows researchers at the Institute to determine which drugs of addiction trigger particular protein responses. The proteomic approach that the Institute adopts allows the researchers there to look at all the proteins in the human body in one go.

Changes in genomic and proteomic (gene and protein) profiles, enables the researchers to examine which particular profiles are associated with particular drugs. Moreover, by examining which genes and proteins are changed in response to drugs of addiction, it is expected that new methods to fight drug addiction will be developed. In particular, by knowing which proteins are switched on by particular drugs such as cocaine, heroin, or morphine, the researchers are able to determine whether there may be ways of blocking the addictive effects of these drugs.

Drug addiction impacts a very large part of American society and addiction to cocaine, heroin, morphine, and other drugs, including prescription drugs, is a persistent part of our culture. Developing new ways to combat addiction, both in the early stages and when it becomes chronic, is critical to help manage the devastating effect that addiction can have on the individuals concerned, their families, and their work colleagues.

The original funding to develop new insights into drug addiction and potentially new therapies came from the offices of National Drug Control Policy, which is in an executive branch of the federal government.

Currently, funding for drug addiction research at the Institute is provided by the Roskamp Foundation.

Traumatic Brain Injury in the War Zone

An article in the New England Journal of Medicine entitled “Traumatic Brain Injury in the War Zone” details the experiences of a supply officer with a US Army Stryker Brigade after suffering a head injury in Northern Iraq in a convoy transporting Iraqi volunteers to Mosul for military training.

The officer reported remembering that the streets were unusually quiet, and he remembered making a radio call to others in the convoy warning them that something might happen. After the vehicle he was traveling in was struck by an improvised explosive device (IED), he remembers having thoughts of why he couldn’t see or hear and remembers wondering where he was. The blast had thrown him from his vehicle, causing a fractured skull and severe contusion of the left fronto-temporal area of his brain.

As one of the most damaging and dangerous consequences of Traumatic Brain Injury (TBI) is brain edema causing swelling of the brain, neurosurgeons performed a craniectomy removing a large piece of skull from the left temporal region, allowing the brain room to swell without being constrained. The compression of the brain in a confined space after a head injury can lead to severe complications, including death.

The next the officer remembers was waking up ten days later at the Walter Reed Hospital. Following treatment, including cognitive and speech therapy, this particular officer made a good recovery, but the article points out that others with similar head injuries do not do as well.

Researchers at the Roskamp Institute (Institute) have previously shown the recovery after TBI is partly controlled by a gene called the APOE gene. Variations in the APOE gene determine whether one will make a good or slow recovery after TBI. It is of interest to note that the same gene determines the risk of developing Alzheimer’s disease in older age groups. APOE may therefore be a general repair gene and current research at the Institute is examining the role of APOE and how it can influence recovery after head injury.

The Institute researchers hope to understand how APOE can, on the one hand increase rates of repair, or on the other hand, encourage degeneration after head injury. Such understanding may lead to the development of new treatments after TBI and may assist young officers, such as the one mentioned here, who suffer the effects of TBI while doing their duty.

This program is funded by the Department of Defense (DoD) as part of the DoD’s general strategy to find new treatments for soldiers who suffer from TBI. TBI is a common occurrence in the civilian population too and treatments developed for military personnel are likely to be extended very quickly for use in civilian population if shown to be successful.

Research On Traumatic Brain Injury At The Roskamp Institute

A recent article in the New England Journal of Medicine emphasizes the important medical consequences of Traumatic Brain Injury (TBI) in US soldiers returning from Iraq. Although the exact number of combat related TBIs is not known, in a survey of over 2500 soldiers returning from Iraq, almost five percent reported injuries with loss of consciousness. A further ten percent reported injuries with altered mental status and seventeen percent reported other injuries during deployment. Importantly, of those reporting loss of consciousness, nearly forty-four percent met criteria for Post Traumatic Stress Disorder (PTSD) and over twenty-seven percent of those reporting altered mental status, also met criteria for PTSD.

The authors conclude that mild TBI, i.e. concussion, occurring among soldiers deployed in Iraq is strongly associated with PTSD and physical health problems three to four months after the soldiers return home. The authors point out that PTSD and depression are important mediators of the relationship between mild TBI and physical health problems.

Researchers at the Roskamp Institute (Institute) are seeking to find new treatments for TBI. In order to do this, they are examining the pathways which are disrupted after TBI to determine which genes and proteins are implicated in pathways of repair or of degeneration. Institute researchers are particularly interested in finding new medications that can intercept the degenerative pathways which occur after TBI. The Institute is devoted to finding new treatments and cures for Alzheimer’s disease (AD) and Institute researchers have a particular interest in the link between AD and TBI.

ABeta as Antiangiogenic drug

Roskamp Institute has previously worked extensively on the ability of amyloid (the main protein that causes Alzheimer’s disease) to stop the growth of blood vessels. Although this is bad news in Alzheimer’s and probably contributes to the decline in cognitive function the effect has been turned to good use in other areas. The Roskamp Institute researchers have shown that amyloid or small fragments of it can stop the growth of blood vessels that supply cancers. It has been known for many years that stopping the growth of blood vessels to cancers can literally starve them of nutrients and arrest their growth or even cause them to shrink. The Roskamp Institute researchers have shown that many cancers are susceptible to having their blood supply cut off. For instance they have shown that amyloid or fragments of it can stop the growth of melanoma, lung cancer and brain tumors. Most recently they have received funding to continue their work with amyloid on lung cancers. They are interested to know whether in addition to stopping the growth of lung cancers amyloid can stop the spread of metastases which so commonly accompany this type of cancer.
Funding from the James & Esther King Biomedical Research Program grant for your project titled will help fund the work for a year and specifically will help to find smaller versions of amyloid that might be suitable for use in humans. One of the challenges that the researchers face is stopping the quick breakdown of amyloid which happens with so many proteins in the blood stream. They plan to alter the basic chemical structure of amyloid to stop it degrading.
The researchers say there is no chance that injecting amyloid can cause Alzheimer’s as it is known in fact that injecting amyloid can be used as a treatment for Alzheimer’s rather than a cause of it.
The award was based on the scientific merit assigned to the proposal by qualified peer reviewers and other factors considered by the Biomedical Research Advisory Council of the State of Florida.

Roskamp Institute examines the cellular responses to biological warfare agents

In September of 2004, the research advisory committee on Gulf War veteran’s illnesses produced a report and recommendation on the scientific progress and understanding the complex condition known as Gulf War Syndrome.

This report suggested that important contributors to Gulf War Syndrome included the nerve agent prophylaxis pill, pyridostigmine bromide, pesticide exposure and potentially anthrax vaccination. One of the recommendations that came out of this committee’s work was that new state-of-the-art technology should be applied to Gulf War Syndrome to try to understand the causes and potential cures of this disorder.

The Roskamp Institute, in collaboration with the Veteran’s Administration (VA), won a grant to pursue this end. The particular approach taken by the Roskamp Institute is to analyze Gulf War Syndrome at the cellular level. To do this, new technology known as proteomics is being used. Proteomic analysis basically allows researchers at the Roskamp Institute to visualize all the proteins which change in a cell after exposure to these potentially toxic agents. In partnership with the Tampa VA, the Roskamp Institute researchers and VA researchers are identifying which proteins characterize exposure to pyridostigmine bromide, organophosphate pesticides and anthrax vaccination.

It will of particular interest to understand which of the proteins that are observed to change after exposure to these agents are specific to the central nervous system. The long-term goal of this project is to understand why Gulf War veterans may be impacted by Gulf War Syndrome and what the underlying biochemical disturbance may be. This in turn, may allow avoidance of Gulf War-type syndromes in the future and may allow VA/Roskamp Institute researchers to consider protection against such syndromes in the event of exposure to nerve agent prophylaxis or pesticides or anthrax vaccination.

Clinical Trials for Alzheimer’s Disease at the Roskamp Institute

The Roskamp Institute is one of many sites nationally that has been chosen to conduct a clinical trial in Alzheimer’s disease using a vaccine approach. Although the mechanism of action of vaccine is unknown, the original idea was that antibodies would circulate in the body and find the amyloid protein in the brain. There are two basic ways to make antibodies appear in the body. One is to give a stimulus protein: in this case the amyloid peptide, which is known as active vaccination or antibodies can be prepared somewhere else and delivered intravenously which is known as passive vaccination.

Original studies conducted by Elan focused on the former approach. Studies carried out in Europe, using an active approach, appeared encouraging in terms of the reduction of pathology of the disease and improved cognition. Unfortunately, however, several patients taking part in the clinical trials with the active vaccine died, most probably due to the vaccination.

At autopsy, it was clear that individuals had suffered a large inflammatory response in their brains. However, importantly, the amyloid deposits, which characterize Alzheimer’s disease, were diminished. This suggested that although the active vaccination was clearly dangerous, it was able to reduce the amyloid load in the brain, which is potentially a cure for Alzheimer’s disease.

A much more controllable way to deliver antibodies for amyloid is by passive vaccination. In this approach, antibodies are prepared outside of the human body and delivered intravenously every few weeks. This approach constitutes the new clinical trial being conducted by Elan Pharmaceuticals, including at the Roskamp Institute site. Although experimental, this approach is likely to be much safer than the active vaccine approach and offers real hope that this amyloid lowering therapy may be able to reduce the cognitive impairment (memory loss, disorientation, etc.) that invariably accompany the disease.

The Roskamp Institute is committed to delivering state-of-the-art therapies for Alzheimer’s disease as they appear on the market or in experimental clinical trials.

Press release for James & Esther King Biomedical Research Program grant

The Roskamp Institute has received an award from the James & Esther King Biomedical Research Program grant for your project titled “Treatment of Lung Adenocarcinoma and Metastasis by Anti-angiogenic Fragments of Abeta.” The award was based on the scientific merit assigned to the proposal by qualified peer reviewers and other factors considered by the Biomedical Research Advisory Council. The official award letter came from the State Surgeon General Ana M. Viamonte Ros. Roskamp Institute researchers have previously shown that the Abeta peptide (also known as amyloid and which causes Alzheimer’s when it accumulates in the brain) is particularly good at stopping blood vessel growth to tumors. The Roskamp Institute researchers have shown that lung cancer growth is severely inhibited by the Abeta peptide. The funding from the state which was awarded after a peer review of the proposal will allow the development of the original findings towards clinical trials with the peptides. The research team are not concerned that if Abeta is used as a treatment for lung cancer it will cause Alzheimer’s because the small protein has in fact been given in human clinical trials as a vaccine prevention of Alzheimer’s.

Genetic manipulation of CD40L reduces Tau phosphorylation

Mainly two cerebral lesions characterized Alzheimer’s disease (AD): an extracellular deposition of the beta-amyloid peptide (Abeta) in senile plaques and an intracellular accumulation of neurofibrillary tangles (principally composed of protein tau). Besides these lesions, a continuous inflammatory state exists in the brain of AD patients.
In AD brains, the tau protein becomes hyper-phosphorylated and acquires a new three-dimensional conformation that results into its aggregation in neuronal cells to form neurofibrillary tangles (NFT). It is generally accepted that the accumulation of Abeta in senile plaques promotes the formation of NFT in AD.
The impact of cerebral inflammation on the aggregation of Abeta has been widely studied. At the Roskamp Institute, it has been previously shown that the binding of CD40 ligand (CD40L) to its receptor CD40, two protein mediating inflammation, is deleterious for AD. Indeed, in the transgenic mouse model for AD Tg2576, disruption of CD40-CD40L binding — by genetic deletion of either CD40 or CD40L, or by a pharmacological treatment — mitigates the amyloid deposition and the associated neuro-inflammation.
In a recent study to be published in Brain Research, the Roskamp Institute reports that the same genetic manipulation (CD40 or CD40L deficiency) in the Tg2576 mouse model for AD reduces the hyper-phosphorylation of the tau protein as well. Interestingly, these data suggest that this decrease is independent than that of Abeta deposition implying that CD40-CD40L pathway has a direct effect on the phosphorylation of tau. Because it would act on the two main pathological features of AD, the therapeutic interest of targeting this pathway is greatly increased by this discovery.

The granulocyte macrophage-colony stimulating factor (GM-CSF) regulates amyloid production

Alzheimer disease is the most common cause of dementia, afflicting 24 million people worldwide. Over time, Alzheimer’s disease gradually destroys a person’s memory and ability to learn and carry out daily activities. In addition; individuals may also experience changes in personality and behavior. Alzheimer disease is accompanied by the presence of amyloid plaques and neurofibrillary tangles in the brain of Alzheimer’s patients with increases in pro-inflammatory cytokines. Beta-amyloid is a key protein shown to play a central role in Alzheimer’s disease etiology. Unfortunately, there is currently no known cure, finding a way to stop Beta-amyloid production and/or increase it degradation will lead to a potentially drug target that can be used to stop the disease. Researchers at the Roskamp Institute showed that inhibition of a Pro-inflammatory cytokine; the granulocyte macrophage colony stimulating factor (GM-CSF) a category of signaling proteins used extensively in cellular communication. GM-CSF has been suggested to induce programmed cell death in the brain tissue of patients with dementia once secreted. Scientist at the Roskamp institute showed that blocking this protein reduce the production of the main pathological protein that causes Alzheimer’s disease (beta-Amyloid) below basal level. In addition the Roskamp Institute scientists examined the mechanism underlying Beta-amyloid reduction after silencing of the receptor protein of G-CSF. Their result show that these effect is due to the fact that blocking the GM-CSF receptor reduce APP (Beta-amyloid protein precursor) trafficking from the cell membrane to the inside of the cell were the preotein in cleaved to generate the beta-Amyloid fragment. The discovery is detailed in an article appears in the journal Cytokine.

Potent antiangiogenic motif in amyloid beta

Roskamp Institute study entitled “Potent anti-angiogenic motifs within the Alzheimer’s β-amyloid peptide” was published in the January 2008 issue of the scientific journal Amyloid. Work by Dr. Michael Mullan and Dr. Daniel Paris showed that a protein central to Alzheimer’s disease pathology is also able to prevent blood vessel growth and stop tumors. In our current study, we investigated whether shorter versions of this same protein could have the same effect. By stopping the blood supply to a tumor, we can effectively starve it and stop cancer. In this study, we have identified a small protein that is able to halt blood vessel growth. Therefore, this short protein has great potential as a novel treatment for cancer.

CD40L induces Abeta production via signaling by the granulocyte macrophage colony stimulating factor (GM-CSF)

Alzheimer’s disease (AD) is the most common type of dementia in the elderly. AD is mainly characterized by the accumulation of a small molecule (known as amyloid beta (Abeta)) in the brain. Many researchers have shown that the molecule CD40L is elevated in AD patients. Roskamp Institute research group headed by Dr. Michael Mullan also have recently shown that CD40L stimulation increases Abeta levels in cellular models of the disease. Furthermore, we have shown that CD40L stimulation of cells that are important for the defense of the nervous system induces increases in pro-inflammatory molecules known as cytokines. The granulocyte macrophage colony stimulating factor (GM-CSF) is one of these cytokines involved in inflammation responses in the brain. Numerous studies have correlated AD with increases in pro-inflammatory cytokines. In the cytokine paper, we have shown that CD40L stimulation increases the levels of both GM-CSF and Abetain AD cell models. We have shown that treatment of these cells with GM-CSF causes a time dependent significant increase in Abeta levels. We demonstrate that blocking GM-CSF reduces CD40L-induced Abeta production in a dose dependent manner. In addition, we show that inhibiting GM-CSF signaling by silencing the GM-CSF receptor gene significantly reduces Abeta levels to below basal levels in non-CD40L-stimulated by blocking the trafficking of Abeta’s mother protein, the amyloid precursor protein. Our results that are now published in the Journal cytokine (Volmar et al., in press) suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Abeta production.

Potent anti-angiogenic motifs within the Alzheimer beta-amyloid peptide

A study entitled “Potent anti-angiogenic motifs within the Alzheimer’s β-amyloid peptide” was published in the January 2008 issue of the journal Amyloid. Building on previous work showing that the Alzheimer’s Aβ peptide is able to prevent blood vessel growth and inhibit tumor growth, Roskamp Institute scientists investigated particular sequences within the Alzheimer’s Aβ peptide in order to identify whether short derivatives of Aβ are able to have the same effect. Inhibition of blood vessel growth is an attractive approach for preventing tumorigenesis since tumors need an adequate blood supply to grow beyond a certain size. Using different fragments of the Aβ peptide, we have identified, for the first time, a critical 8 amino acid sequence within the Aβ peptide, HHQKLVFF, which is able to block blood vessel growth. This short peptide has potential therapeutic relevance for the prevention of tumor growth.

For more details read the journal article at:
Patel NS, Quadros A, Brem S, Wotoczek-Obadia M, Mathura VS, Laporte V, Mullan M, Paris D. Amyloid. 2008 Mar;15(1):5-19.

Effect of NSAIDS on cognitive ability of Alzheimer’s Patients

Medications that reduce inflammation known as non-steroidal anti-inflammatory drugs (NSAIDS) do not improve thinking abilities in normal seniors. These findings from the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) were published this month in Archives of Neurology. The Roskamp Institute Memory Clinic in Tampa was one of a handful of centers across the United States that took part in this study that was supported by the Federal Government. The Tampa clinic enrolled over 400 seniors (age 70 or older) with at least one relative with a dementia. The group was studied for 5 years, undergoing memory testing every year. Two-thirds of the participants received NSAIDS, either Naproxen, or Celecoxib, and one- third, a sugar pill. The study reports that one of the treatments (Naproxen) may contribute to worsening memory or other mental abilities. However further study is needed to determine if these finding persists over time, or if seniors who performed worse on memory testing were experiencing the early signs of a dementia.Drs. Cheryl Luis and Timothy Crowell, specialists in Neuropsychology, supervised the day-to-day aspects of the study in Tampa. Dr. Michael Mullan, director of the Roskamp Institute and principal investigator.

NSAIDS and their effect on Alzheimers disease

Non-steroidal anti-inflammatory (NSAIDS) drugs such as Naproxen and Celecoxib do not improve cognition in at-risk older adults. These findings from the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT) were published this month in Archives of Neurology.  The Roskamp Institute Memory Clinic in Tampa was one of a handful of centers across the United States that took part in this primary prevention trial funded by the National Institute of Aging. The Tampa site enrolled over 400 subjects, age 70 or older with a reported family history of Alzheimer’s-like dementia.  During the 5-year study period, participants underwent annual cognitive testing and were randomly assigned to one of two treatments (Naproxen 220 mg twice daily, Celecoxib 220 mg twice daily) or a placebo. Although treatment was suspended in 2004, following a report of increased cardiovascular risk in another prevention trial, subjects continued annual follow-up.  Results examining the cognitive data collected up to 6 months after treatment was discontinued suggest that Naproxen may in fact have a small deleterious effect on cognition. However further study is needed to determine if this effect is mitigated or exaggerated over time, or if results were influenced by subjects who may have been in the early stage of a dementia. Drs. Cheryl Luis and Timothy Crowell, specialists in Neuropsychology, supervised the day-to-day aspects of the study in Tampa. Dr. Michael Mullan, director of the Roskamp Institute and principal investigator for the Tampa site served on the writing committee of the manuscript. Go to http://www.ncbi.nlm.nih.gov/pubmed/18474729 for more information.

    Keywords:
  • alzheimers disease
  • alzheimers disease assessment scale
  • alzheimers disease end stage
  • alzheimers disease symptoms
  • symptoms of alzheimers disease
  • alzheimers disease and
  • alzheimers disease articles
  • alzheimers disease care
  • alzheimers disease diagnosis
  • alzheimers disease fact
  • alzheimers disease help
  • alzheimers disease info
  • alzheimers disease information
  • alzheimers disease photos
  • alzheimers disease picture
  • alzheimers disease stage
  • alzheimers disease statistics
  • alzheimers disease support
  • alzheimers disease test
  • alzheimers disease type
  • dementia alzheimers disease
  • information on alzheimers disease
  • prevent alzheimers disease
  • symptom of alzheimers disease
  • treatment for alzheimers disease
  • alzheimer’s disease statistics
  • alzheimer’s disease assessment
  • alzheimer’s disease
  • early onset alzheimer’s disease
  • what is alzheimer’s disease
  • alzheimer’s disease assessment scale
  • alzheimer’s disease information
  • information on alzheimer’s disease
  • alzheimer’s disease articles
  • alzheimer’s disease drug
  • alzheimer’s disease and dementia
  • alzheimer’s disease diagnosis
  • alzheimer’s disease info
  • alzheimer’s disease treatment
  • alzheimer’s disease treatments
  • causes of alzheimer’s disease
  • stages of alzheimers
  • signs of alzheimers
  • stage of alzheimers
  • early signs of alzheimers
  • sign of alzheimers
  • brain injury
  • mild brain injury
  • traumatic brain injury
  • mild traumatic brain injury
  • trumatic brain injury
  • beta amyloid
  • beta amyloid antibody
  • anti beta amyloid antibodies
  • anti beta amyloid antibody
  • beta amyloid antibodies
  • alzheimers
  • alzheimers association
  • what is alzheimers
  • diagnosing alzheimers
  • dementia vs alzheimers
  • aluminum alzheimers
  • information on alzheimers
  • alzheimers donation
  • alzheimers memory walk
  • aids alzheimers
  • alzheimers assoc
  • alzheimers com
  • alzheimers desease
  • alzheimers picture
  • alzheimers signs
  • alzheimers test
  • alzheimers testing
  • alzheimers treatments
  • alzheimers walk
  • early alzheimers
  • end stage alzheimers
  • familial alzheimers
  • alzheimers activity
  • alzheimers and parkinsons disease
  • alzheimers bracelet
  • alzheimers brain disease
  • alzheimers drug treatment
  • alzheimers drugs
  • alzheimers help
  • alzheimers information
  • alzheimers organization
  • alzheimers patients
  • alzheimers screening
  • alzheimers store
  • alzheimers symptom
  • alzheimers symptoms
  • book on alzheimers
  • cure for alzheimers
  • alzheimer s disease
  • amyloid disease
  • alzheimer disease
  • cardiovascular disease
  • disease
  • vascular disease
  • celiac disease
  • coronary artery disease
  • disease symptoms
  • dementia disease
  • parkinson disease
  • parkinsons disease
  • alzheimer disease history
  • blood disease
  • crohns disease
  • stages alzheimer disease
  • about alzheimer’s
  • alzheimer’s association
  • alzheimer’s info
  • alzheimer’s information
  • alzheimer’s statistics
  • alzheimer’s treatments
  • coping with alzheimer’s
  • activities for alzheimer’s patients
  • alzheimer’s activities
  • alzheimer’s research
  • alzheimer’s society
  • alzheimer’s stages
  • alzheimer’s symptoms
  • early signs of alzheimer’s
  • alzheimer’s treatment
  • early onset alzheimer’s
  • treatment for alzheimer’s
  • treatments for alzheimer’s
  • what is alzheimer’s
  • alzheimer’s
  • alzheimer’s stages of
  • alzheimer’s diagnosis
  • alzheimer’s diseases
  • information on alzheimer’s
  • alzheimer’s bracelet
  • alzheimer’s care facilities
  • alzheimer’s caregivers
  • alzheimer’s cure
  • alzheimer’s drugs
  • alzheimer’s news
  • alzheimer’s signs
  • alzheimer’s support
  • alzheimer’s support groups
  • alzheimer’s test
  • alzheimer’s therapy
  • alzheimer treatment
  • alzheimer treatments
  • alzheimer society
  • what is alzheimer
  • alzheimer
  • alzheimer s
  • alzheimer association
  • alzheimer symptoms
  • alzheimer test
  • activities for alzheimer
  • activities for alzheimer patients
  • alzheimer care
  • alzheimer diagnosis
  • alzheimer foundation
  • alzheimer information
  • alzheimer research
  • alzheimer support groups
  • early onset alzheimer
  • dementia
  • dementia activities
  • dementia stages
  • dementia care
  • dementia symptoms
  • symptoms of dementia
  • what is dementia
  • vascular dementia
  • dementia support
  • early dementia
  • frontal lobe dementia
  • lewy body dementia
  • stages of dementia
  • dementia research
  • early onset dementia
  • elderly dementia
  • senile dementia
  • amyloidosis
  • head trauma
  • roskamp institute
  • brain injuries
  • amyloid
  • diseases
  • head injuries
  • brain stem injury
  • cardiovascular diseases
  • head injury
  • closed head injury
  • amyloid antibody
  • roskamp
  • amyloid antibodies
  • amyloid diseases
  • brain tumor
  • brain trauma

Anti-hypertension Drugs and Alzheimers

Alzheimers Disease is afflicting millions world wide and the cost of care runs in several billions. Researchers are working hard to find a cure for Alzheimers Disease. Roskamp Insititute, Sarasota, Florida is currently doing clinical trials with Nilvadipine (an anti-hypertension drug that blocks L-type Calcium Channels) in Ireland. Several research is being also conducted to test hypertension drugs as cure for Alzheimers. Pasinetti — who works at New York’s Mount Sinai School of Medicine recently reported their observation regarding anti-hypertension drug and its effects on Alzheimer’s Disease.

The Roskamp Institute is Participating in a New Phase III MS Study

Genetic Engineering and Biotechnology News has the scoop on a new study the Roskamp Institute is conducting. Here are the details:

SARASOTA, Fla., April 30 /PRNewswire/ — The Roskamp Institute announced today that it is now screening patients for enrollment in a new Phase III study to evaluate the efficacy and safety of FTY720 (fingolimod), a novel, investigational, once-daily, oral medication, in relapsing-remitting multiple sclerosis (RRMS). The 12-month, double-blind, randomized, active-comparator study, called “TRANSFORMS” (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS) is sponsored by Novartis and will include approximately 1275 MS patients in more than 170 study centers worldwide.

“If the Phase III study program confirms the data demonstrated in the Phase II study program and leads to FDA approval, FTY720 may represent an improvement when compared to currently-available injectable medications,” said
Dr. Andrew Keegan, Principal Investigator.

Here are the full details.

alzheimers michael mullan