Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging

Authors


Abstract

Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age. 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 in 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 insult. These phenotypes recapitulate defects in NSPCs during aging, giving rise to the possibility that Nampt-mediated NAD+ biosynthesis is a mediator of age-associated functional declines in NSPCs.

Synopsis

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Levels of NAD+ and the NAD+ biosynthetic enzyme Nampt decline in the hippocampus during aging. Nampt ablation in adult neural stem/progenitor cells reduces self-renewal, proliferation, and oligodendrogenesis. Age-associated decreases in the stem cell pool are reversed by the administration of nicotinamide mononucleotide, a key NAD+ intermediate.

  • Nampt is expressed in adult neural/progenitor stem cells and is the main source of their NAD+ levels.
  • Loss of Nampt reduces proliferation by stalling progression of the neural stem/progenitor cell cycle at G0/G1.
  • The NAD+-dependent sirtuins Sirt1 and Sirt2 redundantly mediate neural stem/progenitor cell fate decisions into oligodendrocytes.
  • Loss of Nampt reduces neural stem/progenitor cell-derived oligodendrocyte regeneration after cuprizone-induced demyelination.

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