Investigation of impaired neural stem cell activation in Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是一种破坏性的神经退行性疾病，可导致大脑 海马区。哺乳动物海马齿状回中含有静止的神经细胞。 干细胞(NSCs)可以重新进入细胞周期并分化为功能性兴奋性神经元。这 神经发生过程支持学习和记忆功能，以及健康的情绪调节。 然而，在衰老和阿尔茨海默病中，神经发生水平急剧下降，在啮齿动物身上的研究表明 神经发生水平和认知表现之间的功能联系。尽管静止的NSC是 对于新神经元的来源，目前对这些细胞在AD中是如何受到影响的了解极其有限。 初步研究表明，在阿尔茨海默病小鼠模型中，静止的神经干细胞存在缺陷。此外，这些细胞是 特别容易在衰老过程中受到损害，这是AD的最大风险因素。这项提议需要 综合的多组学方法，以解决AD中静止池如何受到影响的关键问题。 使用已建立的小鼠模型和人类组织，特定目标1将定义转录和 阿尔茨海默病单细胞水平上的表观基因组变化。AIM 2的工作将利用代谢组学来充分阐明 在AD中发生的代谢变化。最后，Aim 3将使用功能转录定位屏幕 在静止的神经干细胞中的中央通路，以确定这些细胞如何在AD中选择性地脆弱。把这个放在一起 这项工作将全面了解阿尔茨海默病小鼠模型中休眠的神经干细胞是如何受到影响的 在人体组织中也是如此。这项研究将为神经退行性变社区提供关键数据， 用于功能研究和开发干预措施以预防、治疗甚至治愈 从长远来看，神经退行性变。

PROJECT SUMMARY Alzheimer’s Disease (AD) is a devastating neurodegenerative disease that causes severe atrophy in the hippocampal area. The dentate gyrus of the mammalian hippocampus harbors populations of quiescent neural stem cells (NSCs) that can re-enter the cell cycle and differentiate into functional excitatory neurons. This process of neurogenesis supports learning and memory functions, as well as healthy mood regulation. However, in aging and AD, levels of neurogenesis sharply decline, and work in rodents has demonstrated a functional link between levels of neurogenesis and cognitive performance. Although quiescent NSCs are the source of new neurons, the current understanding of how these cells are impacted in AD is extremely limited. Preliminary work shows that quiescent NSCs are defective in a mouse model of AD. Moreover, these cells are particularly vulnerable to damage during aging, which is the greatest risk factor for AD. This proposal takes an integrated, multiomics approach to address the critical question of how the quiescent pool is affected in AD. Using a well-established mouse model and human tissue, specific Aim 1 will define the transcriptomic and epigenomic changes at the single cell level in AD. Work in Aim 2 will employ metabolomics to fully elucidate the metabolic changes that occur in AD. Lastly, Aim 3 will use a functional transcriptomics screen targeting central pathways in quiescent NSCs to identify how these cells are selectively vulnerable in AD. Together this work will result in a comprehensive understanding of how dormant NSCs are affected in a mouse model of AD as well as in human tissue. This study will provide key data to the neurodegeneration community that can be leveraged for functional studies and the development of interventions to prevent, treat and even cure neurodegeneration in the long term.