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

阿尔茨海默氏病神经干细胞活化受损的研究

• 批准号: 10624857
• 负责人: Ashley E Webb
• 金额: $ 40.41万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624857
• 关键词: 3xTg-AD mouse; ATAC-seq; Ablation; Acceleration; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Area; Atrophic; Autopsy; Brain; Brain Injuries; CRISPR screen; CRISPR/Cas technology; Cell Cycle; Cell Differentiation process; Cell Nucleus; Cell division; Cells; Chromatin; Communities; Cytoplasmic Granules; Data; Disease; Epigenetic Process; Future; Gene Expression; Genes; Genetic Transcription; Genomic approach; Goals; Hippocampus; Human; Human Pathology; Image; Impaired cognition; Impairment; Individual; Intervention; Investigation; Knowledge; Late Onset Alzheimer Disease; Learning; Link; Memory; Memory Loss; Metabolic; Methods; Mitochondria; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathway interactions; Population; Process; Resolution; Risk Factors; Rodent; Sampling; Source; Time; Work; aging brain; candidate identification; cognitive performance; dentate gyrus; entorhinal cortex; epigenomic profiling; epigenomics; excitatory neuron; experience; functional disability; functional genomics; gene network; healthy aging; human tissue; improved; interest; metabolomics; mood regulation; mouse model; multiple omics; nerve stem cell; neurogenesis; prevent; ratiometric; self-renewal; single nucleus RNA-sequencing; stem cell function; stem cell population; therapy development; transcriptomic profiling; transcriptomics

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.

项目摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其导致大脑中的严重萎缩。 海马区哺乳动物海马的齿状回含有大量的静止神经元， 干细胞（NSC）可以重新进入细胞周期并分化为功能性兴奋性神经元。这 神经发生的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AD中，神经发生的水平急剧下降，在啮齿动物中的工作已经证明了神经发生的水平。 神经发生水平和认知表现之间的功能联系。虽然静止的神经干细胞是 由于新神经元的来源，目前对这些细胞在AD中如何受到影响的理解非常有限。 初步研究表明，静止的神经干细胞在AD小鼠模型中是有缺陷的。此外，这些细胞是 特别容易在衰老过程中受损，这是AD的最大风险因素。这项建议需要一个 集成的，多组学的方法来解决的关键问题，如何在AD的静态池受到影响。 使用良好建立的小鼠模型和人组织，特异性Aim 1将定义转录组学， AD中单细胞水平的表观基因组变化。目标2的工作将采用代谢组学来充分阐明 发生在AD中的代谢变化。最后，Aim 3将使用功能性转录组学筛选靶向 在静止的神经干细胞的中枢通路，以确定这些细胞是如何选择性地在AD脆弱。一起这么 这项工作将全面了解休眠的神经干细胞在AD小鼠模型中是如何受到影响的 以及在人体组织中。这项研究将为神经变性社区提供关键数据， 用于功能研究和开发预防、治疗甚至治愈的干预措施 神经退行性变的长期趋势