乙醛脱氢酶2（ALDH2）对阿尔茨海默病认知障碍的保护作用及其机制研究

More and more evidence shows that aldehyde dehydrogenase-2 (ALDH2) is the key mediator of endogenous cytoprotection. It's reported that ALDH2 gene deficiency results in an elevated incidence of Alzheimer's Disease (AD), and ALDH2-knockout mice are more susceptible to oxidative stress injury, age-related neurodegenerative diseases and amnesia. Is ALDH2 able to improve the cognitive dysfunction and achieve the neuroprotection in AD? And what are the specific mechanisms and the pivotal signal pathway? Our previous studies showed that ALDH2 overexpressed AD mice took a considerable advantage over AD mice in learning and memorizing. Furthermore, ER stress-related protein pIRE1a/IRE1a, which is elevated in AD mice, was significantly down-regulated in ALDH2 overexpressed AD mice.It indicated that ALDH2 may exert anti-apoptosis effect and improve cognitive dysfunction by reducing some ER stress key signal molecules in AD mice. In this project, the ALDH2 overexpressed AD mouse will be used which is our lab's initiative. To give a deep insight into the molecular mechanism of neuroprotective effect of ALDH2 on improving cognitive dysfunction in AD, the methods such as behavior study, histology, cell biology and physiology will be used. The study will provide firsthand evidence for the application of ALDH2 and broaden the new concepts in discovering drugs in AD treatment.

越来却多的证据表明，ALDH2是介导细胞内源性保护的关键物质。据报道，ALDH2基因缺失增加患AD的危险性，ALDH2敲除小鼠更易遭受氧化应激损伤、出现增龄相关神经退行性病理改变及记忆力丧失。然而ALDH2能否改善AD认知功能障碍、实现神经细胞保护？其机制及关键信号分子是什么？国内外未见报道。我们的预实验结果提示：ALDH2过表达AD小鼠的认知功能明显高于AD小鼠；同时发现AD小鼠增高的内质网应激相关蛋白pIRE1a/IRE1a在ALDH2过表达AD小鼠显著下调，提示ALDH2可能通过降低AD小鼠ER Stress某些关键信号分子抗凋亡、改善认知障碍。本研究拟应用国际首创的ALDH2过表达AD小鼠模型，从行为学、组织学、细胞生物学、生理学等多方位、全面深入探讨ALDH2对AD认知功能障碍的保护作用及其分子机制。为ALDH2应用于AD治疗提供直接证据，为AD药物研发开拓崭新思路和靶点。

越来却多的证据表明，ALDH2是介导细胞内源性保护的关键物质。据报道，ALDH2基因缺失增加患AD的危险性，ALDH2敲除小鼠更易遭受氧化应激损伤、出现增龄相关神经退行性病理改变及记忆力丧失。然而ALDH2能否改善AD认知功能障碍、实现神经细胞保护？其机制及关键信号分子是什么？国内外未见报道。我们的预实验结果提示：ALDH2过表达AD小鼠的认知功能明显高于AD小鼠；同时发现AD小鼠增高的内质网应激相关蛋白pIRE1a/IRE1a在ALDH2过表达AD小鼠显著下调，提示ALDH2可能通过降低AD小鼠ER Stress某些关键信号分子抗凋亡、改善认知障碍。本研究拟应用国际首创的ALDH2过表达AD小鼠模型，从行为学、组织学、细胞生物学、生理学等多方位、全面深入探讨ALDH2对AD认知功能障碍的保护作用及其分子机制。为ALDH2应用于AD治疗提供直接证据，为AD药物研发开拓崭新思路和靶点。