Pleiotrophin ameliorates age-induced adult hippocampal neurogenesis decline and cognitive dysfunction

Cognitive impairment has been associated with an age-related decline in adult hippocampal neurogenesis (AHN). The molecular basis of declining neurogenesis in the aging hippocampus remains to be elucidated. Here, we show that pleiotrophin (PTN) expression is decreased with aging in neural stem and progenitor cells (NSPCs). Mice lacking PTN exhibit impaired AHN accompanied by poor learning and memory. Mechanistically, we find that PTN engages with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) to promote NSPC proliferation and differentiation by activating AKT signaling. PTN overexpression or pharmacological activation of AKT signaling in aging mice restores AHN and alleviates relevant memory deficits. Importantly, we also find that PTN overexpression improves impaired neurogenesis in senescence-accelerated mouse prone 8 (SAMP8) mice. We further confirm that PTN is required for enriched environment-induced increases in AHN. These results corroborate the significance of AHN in aging and reveal a possible therapeutic intervention by targeting PTN.

Automated summary

This study reveals that cognitive impairment is associated with a decline in adult hippocampal neurogenesis (AHN). Pleiotrophin (PTN) expression decreases with aging, leading to impaired AHN and poor learning and memory. The study shows that PTN interacts with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) to promote neural stem and progenitor cell (NSPC) proliferation and differentiation through AKT signaling. Overexpression of PTN or pharmacological activation of AKT signaling in aging mice restores AHN and improves memory deficits.