Molecular mechanisms underlying the preservation of neural stem cell quiescence during aging

摘要

ABSTRACT The R01 parent award aims to investigate the mechanisms that balance neural stem cell (NSC) quiescence and activation during brain aging, and how disruptions in this balance result in a decline in neurogenesis with age. In this supplement to the parent award, we will determine the extent to which activation of quiescent NSCs is defective context of Alzheimer’s disease (AD), and discover the mechanisms responsible. Studies in rodents have shown that activation of quiescent NSC is reduced in the aged brain, resulting in diminished neurogenesis and hippocampus-dependent cognitive function. A number of recent reports indicate that neurogenesis is abundant in the adult human hippocampus. Moreover, similar to rodent models, decreased new neuron formation has been observed in healthy human aging as well as in patients with AD. While previous studies have confirmed a sharp decline in neurogenesis in rodent AD models that recapitulates the human condition, the mechanisms responsible remain unclear. Our overarching hypothesis is that the activation of quiescent NSCs out of the dormant state is defective in AD, resulting in reduced hippocampal neurogenesis. To test our hypothesis, we will use two independent methods to quantify the quiescent NSC pool in an established mouse AD models (3xTg AD). First, we will use a label retaining experiment to quantify the quiescent NSC pool as AD pathology progresses. Second, we will use an in vivo assay of quiescence exit to measure activation of the NSC pool along the same timeline. To begin to discover the mechanisms underlying the changes we observe, we will perform single-nuclei RNA-seq on FACS isolated quiescent and activated NSCs from the mouse AD model. Successful completion of these aims will provide novel insight into the mechanism underlying the decline in neurogenesis in AD. As a result, we expect that this study will contribute to the discovery of new therapeutic approaches to treating Alzheimer’s and other neurodegenerative conditions.