Amyloid-β1-42 oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2

The failure of adult hippocampal neurogenesis is increasingly considered as an important factor in the pathological correlates for memory decline in Alzheimer's disease (AD). Loss of adult-born neurons and abnormalities of neural stem/progenitor cells (NSPCs) within the dentate gyrus (DG) of adult hippocampus might contribute to this process. In this study, we showed that amyloid-beta(1-42) (A beta(42)) oligomer triggers senescent phenotype of NSPCs in vitro. Oligomerized A beta 42 induced the production of senescence-associated biomarkers p16 and senescence-associated beta-galactosidase (SA-beta-gal) in adult mouse hippocampal NSPCs, as well as inhibited cells proliferation and differentiation. In the DG of amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice, the number of senescent NSPCs was significantly increased and senescence-associated protein p16 was upregulated. Formylpeptide receptor 2 (FPR2), one of A beta(42) functional receptors, may be involved in NSPCs senescence. The FPR2 antagonist WRW4 significantly inhibited NSPCs senescence induced by A beta(42). In addition, the activation of p38 mitogen-activated protein kinase (MAPK) in response to the accumulation of reactive oxygen species (ROS) was involved in NSPCs senescence induced by A beta(42). WRW4 inhibited the accumulation of ROS and the activation of p38 MAPK in NSPCs. Our data suggest that A beta(42) accelerates NSPCs senescence via FPR2-dependent activation of its downstream ROS-p38 MAPK signaling, which limits the function of NSPCs and contributes to failure of neurogenesis. This is the first demonstration of NSPCs senescence response to A beta(42).