Background: Abeta deposits represent a neuropathological hallmark of Alzheimer's disease (AD). Both soluble and insoluble Abeta 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 Abeta production or accumulation remains a priority. NFkappaB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Abeta. We therefore explored whether the known NFkappaB inhibitor celastrol could represent a suitable compound for decreasing Abeta production and accumulation in vivo.

Methods: The effect of celastrol on amyloid precursor protein (APP) processing, Abeta production and NFkappaB activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Abeta 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 NFkappaB activation and inhibited BACE-1 expression. Celastrol potently inhibited Abeta1-40 and Abeta1-42 production by reducing the beta-cleavage of APP, leading to decreased levels of APP-CTFbeta and APPsbeta. In vivo, celastrol appeared to reduce the levels of both soluble and insoluble Abeta1-38, Abeta1-40 and Abeta1-42. In addition, a reduction in Abeta 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 Abeta lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFkappaB 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.

---

 

乐备实是国内专注于提供高质量蛋白检测以及组学分析服务的实验服务专家，自2018年成立以来，乐备实不断寻求突破，公司的服务技术平台已扩展到单细胞测序、空间多组学、流式检测、超敏电化学发光、Luminex多因子检测、抗体芯片、PCR Array、ELISA、Elispot、PLA蛋白互作、多色免疫组化、DSP空间多组学等30多个，建立起了一套涵盖基因、蛋白、细胞以及组织水平实验的完整检测体系。

 
我们可提供从样本运输、储存管理、样本制备、样本检测到检测数据分析的全流程服务。凭借严格的实验室管理流程、标准化实验室操作、原始数据储存体系以及实验项目管理系统，已经为超过3000家客户单位提供服务，年检测样本超过100万，受到了广大客户的信任与支持。