利用患者特异的诱导性多能干细胞研究阿尔茨海默病易感基因ADAMTS1的保护性机制

基于患者诱导性多能干细胞（iPS）培养的类脑器官能够在体外模拟人脑的发育过程和结构特点，是研究多种脑疾病的理想模型。申请人的研究关注2019年发表的一项大规模遗传学研究鉴别出了一个新的阿尔茨海默病（AD）风险基因ADAMTS1。在前期研究中已发现ADAMTS1与APP蛋白存在相互作用，抑制Aβ42的产生。对AD患者和健康对照的测序鉴别出一个可以影响该基因表达的启动子区域SNP与AD相关。本研究拟利用申请人建立的类脑器官技术，在iPS分化获得的类脑器官中明确（1）能否通过干预ADAMTS1来减少患者神经细胞Aβ产生；（2）阐明ADAMTS1参与APP切割的分子机制。本研究将有助于理解风险基因ADAMTS1在AD等神经退行性疾病中的作用机制，并为AD的病因学研究及新治疗靶点研发提供参考。

Alzheimer's disease (AD) is one of the most common serious neurodegenerative diseases. the postulated hypothesis that the accumulation of Aβ peptides initiates the pathogenesis of AD has received widespread attention. In recent years, the drug targets identified solely from mouse models lack the potential to be converted into clinical applications, which suggests that we must decipher the origin of pathogenesis and molecular targets based on findings from human studies. A large population-based genome-wide association study published in 2019 identified a new AD-associated gene ADAMTS1, but the function of this gene in the nervous system is unclear. Our previous study found that the metalloproteinase ADAMTS1 interacts with APP protein (APP produces Aβ). APP can be cleaved into a previously unknown fragment by ADAMTS1 overexpression (we name it sAPPats1), and the generation of Aβ42 was inhibited.Cerebral organoids derived from patient specific-iPS by three-dimensional culture may be an ideal disease model of AD. In this study, organoids from AD patients with TTT mutations in the promoter region ofADAMTS1, and organoids with modified gene mutation by CRISPR-Cas9 will be studied to determine: (1) whether AD can be treated by interfering with ADAMTS1 expression level or molecular function, (2) what is the molecular mechanism of ADAMTS1 involved in APP hydrolytic cleavage. This study will contribute to understand the mechanism of risk gene ADAMTS1 in neurodegenerative disease such as AD, and provide a reference for the research of etiological mechanism of AD and the development of new therapeutic targets.