老年血液脂质异常对阿尔茨海默病关键蛋白影响的机制研究

衰老是阿尔茨海默病（AD）最重要的影响因素。研究表明，系统性给予青年小鼠的血浆可以抑制衰老小鼠神经退化。明确血浆中哪些特定的分子或者网络的改变对衰老和AD 的发病起到关键作用，有利于推动AD早期诊断和干预。我们前期临床研究表明，老年人群血浆中血花生四烯酸、水杨酸、甘油磷脂代谢等水平异常和认知障碍的发生相关。Aβ和Tau蛋白是AD发病的关键蛋白，PSEN1和GSK-3β分别是Aβ和Tau通路中的关键酶。本研究假设，衰老可能通过外周血脂质代谢异常干预中枢脂质稳态，改变PSEN1和GSK-3β活性，进而促进Aβ产生和Tau的磷酸化，促进痴呆的发生。我们拟从临床上验证脂质代谢异常对认知障碍的诊断价值，从细胞动物模型上通过调控脂质代谢关键酶ACSL4明确脂代谢对AD关键蛋白的作用，探讨不同脂质饮食对认知障碍干预作用，为AD诊断及干预提供新证据。

Aging is the most important risk factor for developing Alzheimer’s disease. Recent studies found that the plasma of the young mice could rejuvenate the aging process and cognitive impairment in the aging mice. It would be important for us to determine which molecules and network was essentially involved in the aging process and the dementia development. Our preliminary data suggested that, in aging population, the cognition impaired cohort demonstrated abnormal lipid network such as salicylic acid, arachidonic acid, glycerophospholipid metabolism, compared with the cognition normal cohort. Abeta and Tau are the key proteins in AD pathogenesis. Presenilin 1(PSEN1) is the catalytic part of gamma-secretase and responsible for production of Abeta. Glycogen synthase kinase 3 beta (GSK-3β) is a multifunctional serine/threonine kinase, which is the critical phosphorylase for Tau phosphorylation. Based on these evidences, we hypothesize that, aging process results in the abnormal lipid metabolism and impaired lipid network, which in turn might facilitate the AD pathogenesis via regulating the activity of PSEN1and GSK-3β. Therefore, in this study, we will explore the diagnostic value of abnormal lipid metabolism for cognitive dysfunction in aging patients. Besides, we will explore the effect of abnormal lipid metabolism on Aβ production and Tau phosphorylation by specific lipid-rich diet in AD mice model. Our study will provide new evidence for the underlying mechanism in AD and promising intervention in the future.