p75NTR胞外段在阿尔茨海默病发生中的作用和机制研究

Amyloid-beta（Aβ） plays a central role in the pathogenesis of Alzheimer's disease (AD). p75 neurotrophin receptor(p75NTR) mediates Aβ neurotoxicity.We found that:(1)Aβ promotes p75NTR expression,while p75NTR pathway promotes Aβ production,this positive forward feedback loop might lead to Aβover-prodution in AD brain;(2) Extracellular domain of p75NTR(p75NTR-ECD) shedded from membrane p75NTR can attenuate Aβ production and neurotoxicity by blocking p75NTR-Aβ interaction,and attenuate brain Aβ deposition by interferring Aβ aggregation in mouse brain.We propose that release of p75NTR-ECD is a endogenous protective mechanism against Aβ over-production, deposition and neurotoxicity,p75NTR-ECD release disorder may be involved in AD development.This project is to analyze the association of CSF p75NTR-ECD with Aβ,Tau and cognitive status in AD or MCI patients and healthy controls;Then to investigate the mechanism of p75NTR-ECD release disorder in AD brain,and its effects on AD development;Finally to validate p75NTR-ECD as a novel therapeutic target for AD to attenuate Aβ production, neurotoxicity and deposition in the brain.

β淀粉样肽（Aβ）是Alzheimer's病（AD）的核心致病物质。神经营养因子受体p75NTR是介导Aβ神经毒性的关键受体。我们发现:Aβ与p75NTR相互促进,导致Aβ过度产生;p75NTR代谢释放的胞外段（p75NTR-ECD）具有抑制Aβ产生、阻止Aβ聚合和拮抗Aβ神经毒性的作用;AD小鼠脑内p75NTR-ECD释放减少;提出p75NTR-ECD是脑内拮抗Aβ产生、沉积及其神经毒性的保护性机制,p75NTR-ECD释放障碍是AD发生发展的一个重要原因。我们拟首先分析AD患者脑脊液p75NTR-ECD水平同Aβ、Tau和认知功能的相关性,阐明p75NTR-ECD与疾病的相关性;然后从离体和在体探讨p75NTR-ECD释放障碍的机制及对AD发生的影响;最后通过AAV在AD小鼠脑内转染表达分泌人p75NTR-ECD基因,探讨p75NTR-ECD在拮抗Aβ产生、沉积及神经毒性上的防治作用。

β淀粉样肽（Aβ）是 阿尔茨海默病（Alzheimer's disease, AD）的核心致病物质。神经营养因子受体p75NTR是介导Aβ神经毒性的关键受体。我们前期发现Aβ与p75NTR相互促进，导致Aβ过度产生；p75NTR代谢释放的胞外段（p75ECD）具有抑制 Aβ产生、阻止Aβ聚合和拮抗Aβ神经毒性的作用；AD小鼠脑内p75ECD释放减少；提出p75ECD是脑内拮抗 Aβ产生、沉积及其神经毒性的保护性机制，p75NTR-ECD释放障碍是AD发生发展的一个重要原因。通过本项目研究明确了：1）p75ECD的Aβ结合位点，并构建了具有Aβ神经毒性拮抗作用的p75ECD；2）发现AD患者脑内p75ECD水平降低，可以作为AD诊断、鉴别诊断和监测病情严重程度的生物标志物，并揭示p75ECD水平降低的机制在于Aβ对剪切酶TACE的抑制；3）证明通过脑内和外周肌肉转染方法恢复p75ECD水平可显著改善APPswe/PS1dE9转基因小鼠认知功能、减少Aβ产生和沉积、tau蛋白磷酸化、减轻神经变性死亡以及脑内炎症反应，能够有效防治AD；4）提出p75ECD是脑内生理性神经保护分子，可作为阿尔茨海默病防治靶点的新观点