β淀粉样蛋白（Aβ）聚集诱导的神经细胞凋亡是诱发阿尔兹海默症（AD）的主要原因。BACE2作为Aβ前体蛋白（APP）水解过程中重要的分泌酶，其在脑中的作用并不清楚。我们前期研究发现BACE2功能缺失突变的携带者（BACE2G446R）由于丧失对APP的切割能力而引发肠神经系统疾病。近期预实验发现：1）BACE2G446R不能正常切割APP及Aβ前体；2）BACE2G446R多能干细胞分化的脑类器官中积累了大量的Aβ多聚体，并诱导了细胞凋亡；3）在BACE2G446R脑类器官中敲除APP可以缓解神经细胞凋亡的表型。据此我们提出假说：BACE2功能缺失导致对APP切割失衡并丧失了Aβ前体的清除作用，导致Aβ聚集并诱导神经凋亡。本项目拟利用BACE2G446R突变体脑类器官模型，并结合单细胞测序技术，深入研究Aβ积累及诱导细胞凋亡的机制，旨在为有BACE2功能缺失突变的潜在AD患者提供药物靶点。

Neuronal cell apoptosis induced by Amyloid beta (Aβ) accumulation in brain is the major reason for Alzheimer’s disease (AD). BACE2 is one of the critical β-secretase in Aβ precursor protein (APP) cleavage; however, its function in brain nervous system is unclear. Our previous study revealed that the patient carrying BACE2 loss-of-function mutation, like BACE2G446R，will lead to the enteric nervous system disease, due to lose of the ability to process APP. Our preliminary data showed that: 1) BACE2G446R cannot cleave full length of APP and the Aβ precursor; 2) Aβ oligomer accumulation was detected in BACE2G446R hiPSC-derived brain organoids, which resulted in the neuronal cell death; 3) Deletion of APP in BACE2G446R hiPSC-derived brain organoids can rescue these phenotypes, including Aβ accumulation and neuronal cell death. Based on these evidences, we hypothesized that in brain, BACE2 deficiency disrupted the balance for APP processing and failed to clear off the Aβ precursors, which eventually lead to Aβ accumulation and neuronal cell death. In this project, we will further take use of the BACE2G446R hiPSC-derived brain organoid model and the single-cell sequencing technology, to study the mechanisms underlying the Aβ accumulation and neuronal cell death. Through this study, we aim to provide new therapeutic targets for the potential AD patients due to BACE2 deficiency.