Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
Vaccine Research Institute, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
Cell Rep. 2023 Sep 26;42(9):113022. doi: 10.1016/j.celrep.2023.113022. Epub 2023 Aug 22.
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.
认知障碍与成年海马神经发生（AHN）的年龄相关下降有关。衰老海马中神经发生下降的分子基础仍有待阐明。在这里，我们表明，多效蛋白（PTN）的表达在神经干细胞和祖细胞（NSPCs）中随年龄增长而减少。缺乏 PTN 的小鼠表现出 AHN 受损，伴有学习和记忆能力差。从机制上讲，我们发现 PTN 通过激活 AKT 信号转导与蛋白酪氨酸磷酸酶受体 Z1（PTPRZ1）结合，促进 NSPC 的增殖和分化。在衰老小鼠中过表达 PTN 或药理学激活 AKT 信号转导可恢复 AHN 并缓解相关的记忆缺陷。重要的是，我们还发现过表达 PTN 可改善快速老化小鼠 8 号（SAMP8）小鼠受损的神经发生。我们进一步证实，PTN 是丰富环境诱导 AHN 增加所必需的。这些结果证实了 AHN 在衰老中的重要性，并揭示了通过靶向 PTN 进行可能的治疗干预。
