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

衰老过程中保持神经干细胞静止的分子机制

基本信息

批准号：
10288011
负责人：
Ashley E Webb
金额：
$ 39.73万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288011
关键词：
3xTg-AD mouse Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Award Biological Assay Brain Cell Cycle Cell Cycle Arrest Cell Nucleus Cell division Cognition Cognitive Defect Disease Disease Progression Equilibrium Failure Female Gene Expression Genes Hippocampus (Brain)Human Impaired cognition Impairment Individual Intervention Label Lead Learning Link Measures Memory Loss Metabolism Methods Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parents Pathology Patients Reporter Reporting Rodent Rodent Model Small Nuclear RNA Study models Testing TimeLine Work aged aging brain cognitive function combat daughter cell dentate gyrus entorhinal cortex experience experimental study follow-up in vivo insight mouse model nerve stem cell nestin protein neuroblast neurogenesis neuromechanism novel novel therapeutic intervention preservation prevent proteostasis self-renewal tau Proteins transcriptome sequencing

项目摘要

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.

摘要 R01父母奖旨在研究平衡神经干细胞（NSC）静止的机制以及这种平衡的破坏如何导致神经发生的下降，年龄在这个家长奖的补充，我们将确定在多大程度上激活的静态神经干细胞是阿尔茨海默病（Alzheimer's disease，AD）的缺陷背景，并发现了其发病机制.研究啮齿类动物已经表明，在老年大脑中，静止NSC的激活减少，神经发生和依赖于大脑皮层的认知功能。最近的一些报告表明，神经发生在成年人海马体中是丰富的。此外，与啮齿动物模型相似，在健康的老年人以及AD患者中已经观察到新的神经元形成。而先前的研究已经证实了啮齿动物AD模型中神经发生的急剧下降，人类的状况，负责的机制仍然不清楚。我们的首要假设是，在AD中，从休眠状态中激活静止的NSC是有缺陷的，导致降低的海马神经发生为了验证我们的假设，我们将使用两种独立的方法来量化在已建立的小鼠AD模型（3xTg AD）中的静止NSC池。首先，我们将使用标签保留实验，以量化静止的NSC池作为AD病理进展。第二，我们将使用一种体内静止测定退出以测量NSC池沿着相同时间轴的活化。开始发现我们观察到的变化背后的机制，我们将进行单细胞核RNA测序的FACS分离来自小鼠AD模型的静止和激活的NSC。成功实现这些目标将为对AD神经发生下降机制的新见解。因此，我们预计，这项研究将有助于发现新的治疗方法来治疗阿尔茨海默氏症和其他疾病。神经退行性疾病

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age.

DOI：
10.1111/acel.13499
发表时间：
2021-11
期刊：
Aging cell
影响因子：
7.8
作者：
Maybury-Lewis SY;Brown AK;Yeary M;Sloutskin A;Dhakal S;Juven-Gershon T;Webb AE
通讯作者：
Webb AE

Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease.

DOI：
10.1016/j.stemcr.2021.01.019
发表时间：
2021-04-13
期刊：
Stem cell reports
影响因子：
5.9
作者：
Babcock KR;Page JS;Fallon JR;Webb AE
通讯作者：
Webb AE

FOXO3 regulates a common genomic program in aging and glioblastoma stem cells.

DOI：
10.1002/aac2.12043
发表时间：
2021-12
期刊：
Aging and cancer
影响因子：
0
作者：
Audesse, Amanda J;Karashchuk, Galina;Gardell, Zachary A;Lakis, Nelli S;Maybury-Lewis, Sun Y;Brown, Abigail K;Leeman, Dena S;Teo, Yee Voan;Neretti, Nicola;Anthony, Douglas C;Brodsky, Alexander S;Webb, Ashley E
通讯作者：
Webb, Ashley E

Mechanisms of enhanced quiescence in neural stem cell aging.