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

摘要 R01家长奖旨在研究平衡神经干细胞(NSC)静止的机制 和脑老化过程中的激活，以及这种平衡的破坏如何导致神经发生的下降 年龄。在这份家长奖的补充中，我们将确定静止激活的程度 神经干细胞是阿尔茨海默病(AD)的背景缺陷，并发现其发病机制。研究项目： 啮齿动物已经表明，在衰老的大脑中，静止的神经干细胞的激活减少，导致减少 神经发生和海马体依赖的认知功能。最近的一些报告表明， 成年人类的海马体中有丰富的神经发生。此外，与啮齿动物模型类似，减少了 在健康衰老的人和AD患者中都观察到了新的神经元形成。而当 先前的研究证实了啮齿动物AD模型中神经发生的急剧下降，这概括了 在人类状况下，造成这一现象的机制仍不清楚。我们最重要的假设是 在AD中，将静止的NSCs从休眠状态激活是有缺陷的，导致减少 海马神经发生。为了检验我们的假设，我们将使用两种独立的方法来量化 已建立的小鼠AD模型(3xTg AD)中的静态NSC池。首先，我们将使用标签保留 随着AD病理的进展，对静止的NSC池进行量化的实验。第二，我们将使用体内的 静止期退出实验测量NSC池在同一时间线上的激活情况。开始发现 根据我们观察到的这些变化的机制，我们将对分离的FACS进行单核RNA-SEQ 小鼠AD模型中静止和激活的神经干细胞。成功完成这些目标将提供 对阿尔茨海默病神经发生功能下降的潜在机制的新见解。因此，我们预计这一点 这项研究将有助于发现治疗阿尔茨海默氏症和其他疾病的新疗法 神经退行性疾病。

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.