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

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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.

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