脂代谢异常与阿尔茨海默病（AD）发病具有密切关联。临床症状出现前期(PCAD)阶段可观察到老年斑,因此,国际上十分关注发病危险因素和始动因子的研究。申请人首次发现了“老年斑出现前期致病因素与神经退行变化”。并且,还发现脂蛋白水解酶缺乏引起膜的磷脂类组分失稳态,导致突触可塑性障碍。我们前期发现磷脂转运蛋白（PLTP）基因敲除与APP小鼠交配小鼠促进学习认知障碍,但其机制清楚。本项目紧密围绕“阐明PLTPko\APP小鼠如何促使认知障碍的机制”，主要3个方面进行探究：PLTP①是否影响APP代谢及Aβ清除进而诱导过量Aβ的聚集以及相应认知障碍的发生；②否通过调控α-synuclein-SNARE蛋白复合物形成影响突触可塑性及突触功能，导致学习认知功能障碍；③是否通过调控脂代谢及相关的自噬功能导致Aβ毒性聚集以及SNARE蛋白复合物异常，引发认知障碍。这对探究PCAD关键始动因子非常重要。

Alzheimer’s disease and chronic diseases caused by abnormal lipid metabolism are main threats of the life quality of the aged people. It is reported that amyloid pathology occurs in preclinical stage of AD (PCAD), and researches concentrating on the risk factors or initiators of amyloid pathology have attracted a lot of interest. The applicant previously focused on “lipids, arteriosclerosis and brain damage” and first discovered the relationship between neurodegeneration and the risk factors prior to the development of amyloid burden, which served as the beginning of applicant’s research on PCAD. Our previous study on lipoprotein lipase (LPL) found that its deficiency led to the dyshomeostasis of membrane phospholipids and impairment of synaptic plasticity. Moreover, we first observed that phospholipid transfer protein (PLTP) knockout in APP/PS1 transgenic mice exacerbate cognitive dysfunction, but the underlying mechanisms remain unclear. This project aims to unravel the role of PLTP in modulating brain cognitive function and to discover potential therapeutic targets. The project will investigate the following three questions: ①,whether PLTP deficiency promotes the accumulation of Aβ and induces cognitive dysfunction via influencing APP processing and Aβ clearance; ②,whether PLTP deficiency impairs cognitive function through modulating the formation of α-synuclein (α-syn) –SNARE complex and synaptic function; ③,whether PLTP deficiency affects Aβ accumulation and SNARE function by regulating lipid metabolism and autophagy activity. The research on PLTP in the progression of AD could contribute to to identifing early risk factors for AD.