BIN1是继APOE之后LOAD最重要的易感基因。新近证据表明：AD脑内BIN1存在甲基化改变，并可能影响其表达进而调控AD病理进程；但上述甲基化改变是否在AD外周血同样存在，及其参与调控的分子机制目前尚不明确。我们拟在前期建立汉族人群LOAD资源库的基础上，采用外周血单个核细胞，证实BIN1启动子区DNA甲基化状态与AD的易感关联；并通过非定向/定向去甲基化技术，探讨低甲基化对BIN1转录表达的调控。此外，拟运用慢病毒为载体的基因过表达/干扰技术，在细胞和活体层面对BIN1进行靶向干预，观察高表达BIN1及其下游分子对tau蛋白磷酸化的影响，阐明BIN1参与AD病理进程的分子机制；并验证靶向抑制BIN1对自噬信号通路、tau病理、神经元丢失及认知功能障碍的治疗作用。本项目的完成不仅能推动AD表观遗传学认识，更能丰富并完善AD的tau病理发生机制，将为AD预警、诊治和药物研发提供新的靶点。

BIN1 is the most important genetic susceptibility locus in late-onset Alzheimer’s disease (LOAD) after APOE. Recent studies have revealed that brain DNA methylation at BIN1 was changed in AD, which might have an effect on BIN1 expression and thus influence the pathological process of AD. However, whether the DNA methylation changes are also present in peripheral blood of LOAD patients, and its detailed molecular mechanisms in AD pathogenesis are still unknown. Based on the established large samples of Han Chinese LOAD patients, our current researches intend to evaluate the relationship between the methylation status of BIN1 promoter and AD risk in peripheral blood mononuclear cells, and to explore the putative role of DNA hypomethylation in regulation of its transcription and expression levels through nontargeted/ targeted demethylation methods. Then, the regulatory role of BIN1 in autophagy pathway, tauopathy, neuron loss, and cognitive impairment were confirmed by overexpression or silencing of BIN1 using lentivirus vectors in vitro and in vivo. This project will fully reveal the effects of epigenetic modulation on BIN1 levels, and offer a novel target for early warning, diagnosis and treatment of AD via uncovering its underlying molecular pathogenesis.