APP新剪切产物Aη-α调控阿尔茨海默症病理进程的神经毒性机制研究

阿尔茨海默症（AD）病因尚不明确，以β-淀粉样蛋白（Aβ）为靶标的药物试验失败提示主流Aβ假说可能无法全面概括AD发病机理。Aη-α是新发现的Aβ前体蛋白（APP）剪切产物。我们前期发现Aη-α易组装成高神经毒性的寡聚体，还能促进Aβ聚集，海马注射Aη-α可诱导AD小鼠提前出现认知障碍，提示Aη-α可能参与AD病理进程。但Aη-α如何组装、怎样产生神经毒性以及能否调控AD病理进程这些关键问题尚不清楚。本项目拟首先应用分子模拟结合定点突变实验阐明Aη-α寡聚体组装的机制；进一步在细胞、脑片、动物三个层面证明Aη-α寡聚体诱导突触损伤产生神经毒性，通过APP/PS1转基因小鼠海马过表达Aη-α从正面探究其对AD病理进程的调控作用；筛选Aη-α寡聚体抑制剂从反面验证阻止Aη-α毒性、逆转AD病理进程的可行性。研究结果有望明确Aη-α调控AD病理进程的神经毒性机制，为AD药物研发提供新的分子靶标。

The exact course of Alzheimer’s disease (AD) is still unclear. However, the failure of β-amyloid (Aβ)-target anti-AD drugs in the clinical studies indicated that Aβ hypothesis may not be able to fully explain the onset of AD. Aη-α is a novel proteolytic fragment of Aβ precursor protein (APP). We have previously found that Aη-α could assemble into oligomer with high neurotoxicity. Moreover, Aη-α could increase the aggregation of Aβ. Hippocampal injection of Aη-α induced advanced cognitive impairments in AD transgenic mice. These results suggested that Aη-α might play a role in the pathological progress of AD. However, it is still unknown how Aη-α assembles into oligomer, how Aη-α produces neurotoxicity, and whether Aη-α regulates the pathological progress of AD. In this project, the mechanisms underlying the assembly of Aη-α oligomer will be elucidated by using molecular dynamics study and point mutation test. Moreover, Aη-α oligomer-induced neurotoxicity via synaptic impairments will be studied in primary neuronal cultures, hippocampal slices, and normal mice, respectively. Furthermore, the regulation of AD pathological progress by Aη-α will be explored in APP/PS1 transgenic mice with hippocampal over-expression of Aη-α. In addition, Aη-α oligomer inhibitors will be screened. And the disease-modifying effects of Aη-α oligomer inhibitors will be investigated. Our results will not only elucidate the neurotoxic mechanisms of Aη-α underlying the regulation of AD pathological progress, but also provide a novel molecular target for further AD drug development.