Luo Juan, Zou Hailin, Guo Yibo, Huang Ke, Ngan Elly Sau-Wai, Li Peng
Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China.
Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong.
Cell Death Discov. 2022 Feb 2;8(1):47. doi: 10.1038/s41420-022-00845-5.
β-site APP-cleaving enzyme 2 (BACE2) is a homolog of BACE1, which is considered as the most promising therapeutic target for Alzheimer's disease (AD). However, the expression and functional role of BACE2 in central nervous system (CNS) remain obscured. Previously, we identified several BACE2 rare variants in Hirschsprung disease (HSCR) patients and proved that BACE2-mediated APP cleavage might represent a novel HSCR pathogenesis mechanism in enteric nervous system. Here, we validated that these HSCR-associated BACE2 variants were loss-of-function mutations. Using the human pluripotent stem cell (hPSC)-derived brain organoids (BOs), we further demonstrated that BACE2 was mainly expressed in the ventricular zone and cortical plate of BOs, and its expression level was gradually increased along with the BO maturation. Functionally, we found that the BOs carrying the BACE2 loss-of-function mutation (BACE2) showed greater apoptosis and increased levels of Aβ oligomers compared to the control BOs, resembling with the AD-associated phenotypes. All these phenotypes could be rescued via the removal of APP protein in BACE2 BOs. Furthermore, rather than BACE2, BACE2 overexpression in BOs carrying the APP Swedish/Indiana mutations attenuated the AD-associated phenotypes, including Aβ accumulation and neuronal cell death. Taken together, our results unravel that BACE2 can protect the neuronal cell from apoptosis caused by Aβ accumulation, and the deficiency of BACE2-mediated APP cleavage may represent a common pathological mechanism for both HSCR and AD.
β-位点淀粉样前体蛋白裂解酶2（BACE2）是BACE1的同源物，BACE1被认为是阿尔茨海默病（AD）最有前景的治疗靶点。然而，BACE2在中枢神经系统（CNS）中的表达和功能作用仍不清楚。此前，我们在先天性巨结肠病（HSCR）患者中鉴定出了几种BACE2罕见变异，并证明BACE2介导的淀粉样前体蛋白（APP）裂解可能代表了肠神经系统中一种新的HSCR发病机制。在此，我们验证了这些与HSCR相关的BACE2变异是功能丧失性突变。利用人多能干细胞（hPSC）衍生的脑类器官（BOs），我们进一步证明BACE2主要在BOs的脑室区和皮质板中表达，并且其表达水平随着BOs的成熟而逐渐增加。在功能上，我们发现携带BACE2功能丧失性突变（BACE2）的BOs与对照BOs相比，表现出更大程度的细胞凋亡和淀粉样β蛋白（Aβ）寡聚体水平升高，类似于与AD相关的表型。所有这些表型都可以通过去除BACE2 BO中的APP蛋白来挽救。此外，在携带APP瑞典/印第安纳突变的BOs中，过表达BACE2而非BACE2，减轻了包括Aβ积累和神经元细胞死亡在内的与AD相关的表型。综上所述，我们的结果揭示BACE2可以保护神经元细胞免受Aβ积累引起的细胞凋亡，并且BACE2介导的APP裂解缺陷可能代表了HSCR和AD共同的病理机制。
