Genetic manipulation of CD40L reduces Tau phosphorylation

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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.