title: Amyloid-β(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2.
abstract: 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-β(1-42) (Aβ42) oligomer triggers senescent phenotype of NSPCs in vitro. Oligomerized Aβ42 induced the production of senescence-associated biomarkers p16 and senescence-associated β-galactosidase (SA-β-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 Aβ42 functional receptors, may be involved in NSPCs senescence. The FPR2 antagonist WRW4 significantly inhibited NSPCs senescence induced by Aβ42. 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 Aβ42. WRW4 inhibited the accumulation of ROS and the activation of p38 MAPK in NSPCs. Our data suggest that Aβ42 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 Aβ42.
authors.affiliation: 1] School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China [2] Department of Internal Medicine, No. 455 Hospital, Shanghai 200240, China.
authors.forename: N
authors.initials: N
authors.lastname: He
authors.forename: W-L
authors.initials: WL
authors.lastname: Jin
authors.forename: K-H
authors.initials: KH
authors.lastname: Lok
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Yin
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D044042:Receptors, Formyl Peptide; C075222:amyloid beta-protein (1-42); C481578:formyl peptide receptor 2, mouse; C509690:tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide