The role of nicotinamide phosphoribosyltransferase (Nampt) in hippocampal neural stem/progenitor cells

Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).

神经干细胞/祖细胞（Neural stem/progenitor cell, NSPC）的增殖与自我更新，以及损伤诱导的分化能力，均随年龄增长显著下降，但介导这些衰退的分子机制仍不明晰。本研究证实，哺乳动物烟酰胺腺嘌呤二核苷酸（NAD+）生物合成的限速酶——烟酰胺磷酸核糖转移酶（nicotinamide phosphoribosyltransferase, Nampt）与NAD+水平，在海马组织中随年龄增长而降低。成体神经干细胞/祖细胞中Nampt的敲除会在体内减少其细胞池数量与增殖能力。衰老过程中神经干细胞/祖细胞池的缩减，可通过提升海马组织的NAD+水平得以挽救。Nampt是维持神经干细胞/祖细胞NAD+水平的主要来源，且对其细胞周期的G1/S期转换至关重要。Nampt同时通过由Sirt1与Sirt2冗余介导的机制，对少突胶质细胞系的命运决定发挥关键调控作用。成体神经干细胞/祖细胞内Nampt的敲除，会在体内损伤模型中减少神经干细胞/祖细胞介导的少突胶质细胞生成。上述表型重现了衰老过程中神经干细胞/祖细胞的功能缺陷，表明Nampt介导的NAD+生物合成是这些年龄相关功能衰退的调控介质。本研究获取的总RNA来自出生后海马组织来源的神经球，该神经球经体外48小时培养，分别用Nampt特异性抑制剂FK866（10 nM，共4个样本）或溶剂对照（二甲基亚砜，DMSO，1:1000稀释，共4个样本）处理。