硫化孕烯醇酮改善Aβ22823;鼠认知障碍的分子机制研究

项目名称： 硫化孕烯醇酮改善Aβ22823;鼠认知障碍的分子机制研究

项目编号： No.30872725

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 陈玲

作者单位： 南京医科大学

项目金额： 32万元

中文摘要： α#32966;碱能受体（αAChR）是β#28096;粉肽(Aβ#30340;靶蛋白，Aβ19982;αAChR的结合，破坏胆碱能神经系统功能被认为是AD的早期致病机制。本课题主要研究结果显示（1）神经甾体激素硫化孕烯醇酮（PREGS）通过异构上调αAChR能阻断Aβ23545;αAChR的抑制和损害作用，保护αAChR的功能；（2）PREGS通过异构上调αAChR减少Aβ30340;沉积、老年斑的形成；（3）PREGS异构上调αAChR和增强sigma-1受体活性，通过激活PI3K-Akt和ERK-CREB的信号通路阻止Aβ30340;神经毒作用；（4）PREGS异构上调αAChR和增强sigma-1受体活性，能阻止Aβ19979;调PI3K-Akt-mTOR-p70S6k信号分子通路，保护新生神经元的突起生长和存活。（5）PREGS异构上调αAChR和增强sigma-1受体活性改善AD的认知功能。本研究结果不仅为内源性甾体激素能用于AD的预防提供理论依据，同时提出选择性干预αAChR与Aβ32467;合以预防和治疗AD的新思路。

中文关键词： 阿尔茨海默病;β#28096;粉肽;神经甾体激素硫化孕烯醇酮;α#32966;碱能受体;sigma-1受体

英文摘要： Alzheimer's disease (AD) is characterized by a progressive neurodegeneration leading to dementia and death. The accumulation and deposition of βmyloid (Aβwithin the brain is thought to be the primary force driving the pathogenesis of AD. In particular, the high-affinity binding of Aβo αnicotinic acetylcholine receptor (αAChR) not only impairs the function of a7nAChR but also facilitates endocytosis and accumulation of Aβn neuronal cells resulting in the impairment of spatial memory. The present study focused on exploring the effects of neurosteroid pregnenolone sulfate (PREGS), in comparison with the selective agonists of sigma-1 receptor (σ) and αAChR, on the cognitive deficits and the death of pyramidal cells in 8-month-old male APPswe/PS1dE9 transgenic (APP/PS1) mice and Aβ-35-mice. Our results in the present study showed (1) the cognitive deficits in either APP/PS1 mice or Aβ-35-mice could be improved by the treatment with neurosteroid PREGS in a dose-dependent manner; (2) PREGS up-regulating αAChR could protect the function of αAChR against Aβnduced damage; (3) PREGS could attenuate the accumulation of Aβnd the formation of amyloid plaques in APP/PS1 mice; (4) the anti-amnesic effects of PREGS in Aβ-35-mice was thought to be depend on the neuroprotection of σ- and αAChR-mediated PI3K-Akt and ERK-CREB signaling pathways; (5) PREGS was able to prevent Aβmpaired survival and dendritic growth of newborn neurons through σ-mediated modulation of PI3K-Akt-mTOR-p70S6k signaling against the Aβnduced down-regulation of Akt, mTOR and p70S6k. In summary, the effects of αAChR agonists or the σ agonists on the Aβnduced impairment of learning and memory have been reported in Alzheimer's disease pertain, APP/PS1 mice and Aβ-35-mice. This study provides a new insight that PREGS targeting αAChR and σ against Aβeurotoxicity may have substantial benefit for the prevention and treatment of Alzheimer's disease.

英文关键词： Alzheimer's disease (AD);βmyloid (Aβ neurosteroid pregnenolone sulfate (PREGS); αnicotinic acetylcholine receptor (αAChR);sigma-1 receptor