APP and Alzheimer disease: Meanwhile, to investigate whether the neuronal apoptosis in BACE2G446R organoids was caused by the loss of BACE2-mediated APP cleavage activity, immunostaining assay was performed using Aβ oligomer antibody and the results revealed that lots of Aβ oligomers were detected in BACE2G446R organoids compared to control group (Fig. 3F, G), suggesting the alteration of BACE2-mediated APP cleavage in HSCR-associated BOs resulted in enhanced Aβ oligomer accumulation and induced the neuronal cell apoptosis, resembling with the AD-associated phenotypes.