阿尔茨海默疾病（Alzheimer’s disease，AD）是一种最易在老年群体发病并引起记忆功能障碍的神经退行性疾病。研究表明，β-淀粉样多肽寡聚体（Aβo）通过间接激活胞内蛋白激酶PAR-1/MARK和AMPKα，磷酸化Tau蛋白上与微管网架结合序列内的Ser262/Ser356位点，诱发Tau错误转位至树突棘内，引起突触损伤，造成了AD记忆功能障碍。本项目根据Tau蛋白 Ser262位点前后一段氨基酸序列设计竞争性穿膜干扰短肽，结合运用离体蛋白免疫印迹、免疫组化、电生理以及在体行为学的实验方法检测这一干扰短肽能否通过竞争性阻断PAR-1/MARK和AMPKα对Tau Ser262/Ser356的磷酸化，改善Aβo 引起的突触损伤及APP/PS1双转基因小鼠记忆功能障碍。本项目将为以Tau蛋白Ser262/Ser356磷酸化为靶点设计改善AD记忆功能障碍的药物提供一定的试验依据。

Alzheimer's disease (AD) is the leading cause of dementia in the eldly. A wealthy of evidence suggests that amyloid-beta oligomers (Aβo) can indirectly activate intracellular protein kinase PAR-1/MARK and AMPKα to phosphorylate Tau Ser262/Ser356 site in its Tubulin-binding sequence, and the phosphorylated Tau mislocalizes into spines and induces synaptic dysfunction, which finally leads to AD memory deficits. This project is aimed to design a cell-permeable specific interfering peptide that flanks Tau Ser262 residue, and in vitro western blotting, immunohistochemistry, electrophysiology, and in vivo behavioral methods are combined to illustrate whether this peptide could ameliorate Aβo-induced synaptic dysfunction as well as memory deficits of APP/PS1 transgenic mice via competitively inhibiting phosphorylation of Tau S262/Ser356 site by PAR-1/MARK and AMPKα. Our study will give some experimental clues on using Tau S262/Ser356 phosphorylation as a target for pharmacological treatment of AD memory deficits.