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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   G446R  ) 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   G446R   BOs. Furthermore, rather than  BACE2   G446R  ,  BACE2   WT   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.

BACE2 variant identified from HSCR patient causes AD-like phenotypes in hPSC-derived brain organoids