Involvement of p38 in Age-Related Decline in Adult Neurogenesis via Modulation of Wnt Signaling

Abstract

Summary: Neurogenesis in specific brain regions in adult mammals decreases with age. Progressive reduction in the proliferation of neural stem and progenitor cells (NS/PCs) is a primary cause of this age-associated decline. However, the mechanism responsible for this reduction is poorly understood. We identify p38 MAPK as a key factor in the proliferation of neural progenitor cells (NPCs) in adult neurogenic niches. p38 expression in adult NS/PCs is downregulated during aging. Deletion of p38α in NS/PCs specifically reduces the proliferation of NPCs but not stem cells. Conversely, forced expression of p38α in NS/PCs in the aged mouse subventricular zone (SVZ) restores NPC proliferation and neurogenesis, and prevents age-dependent SVZ atrophy. We also found that p38 is necessary for suppressing the expression of Wnt antagonists DKK1 and SFRP3, which inhibit the proliferation of NPCs. Age-related reduction in p38 thus leads to decreased adult neurogenesis via downregulation of Wnt signaling. : Kase et al. show that p38 expression in neural stem and progenitor cells (NS/PCs) in the adult brain decreases with aging. This reduction specifically causes proliferation defect in neural progenitor cells (NPCs), leading to the age-dependent decline of adult neurogenesis. Conversely, overexpression of p38α in NS/PCs in the aged brain restores NPC proliferation without exhaustion of neural stem cells. Key words: adult neurogenesis, aging, DKK1, neural progenitor cell, neural stem cell, p38, SFRP3, transit-amplifying cell, Wnt signaling