Presenilin 2 regulates corticosterone-induced autophagic death of adult hippocampal neural stem cells

Chronic psychological stress is a well-known risk factor for neurodegenerative diseases including Alzheimer disease (AD), yet the underlying mechanisms remain unclear. We previously showed that chronic stress impairs adult hippocampal neurogenesis by triggering autophagic cell death of adult hippocampal neural stem (HCN) cells. Impairment of adult hippocampal neurogenesis is widely observed in the brains of human AD patients and animal models. However, it remains unknown whether stress-induced death of HCN cells is related to the pathogenesis of AD. In this study, we investigated whether the stress hormone, corticosterone (CORT) induces HCN cell death through presenilin 2 (<i>Psen2</i>), a gene associated with familial AD. Using CRISPR/Cas9-based knockout models and in vitro CORT treatment, we found that <i>Psen2</i> expression is upregulated by CORT and <i>Psen2</i> deletion prevents CORT-induced death in HCN cells. However, the <i>Psen2</i> N141I mutation, despite its pathogenicity in AD, did not exacerbate CORT-induced cell death in vitro and hippocampus-dependent behavioral deficits in vivo. These findings indicate that while <i>Psen2</i> is essential for stress-induced death of HCN cells, the <i>Psen2</i> N141I mutation alone may not be sufficient to link chronic stress to AD pathogenesis.