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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' 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

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.

抽象的 R01家长奖旨在研究平衡神经干细胞（NSC）静止的机制 大脑衰老过程中的激活和激活，以及这种平衡的破坏如何导致神经发生的下降 在此对家长奖励的补充中，我们将确定激活静止状态的程度。 NSCs 是阿尔茨海默病 (AD) 的缺陷背景，并发现了相关机制。 啮齿类动物的研究表明，衰老大脑中静态 NSC 的激活减少，导致 最近的一些报告表明，神经发生和海马依赖性认知功能。 成人海马体中的神经发生丰富，而且与啮齿动物模型相似，神经发生减少。 在健康的人类衰老过程中以及 AD 患者中都观察到了新的神经元形成。 先前的研究已经证实，啮齿动物 AD 模型中神经发生急剧下降，这概括了 人类状况下，其机制仍不清楚，我们的首要假设是 在 AD 中，将静止的 NSCs 从休眠状态激活出来是有缺陷的，从而导致 AD 患者的 为了检验我们的假设，我们将使用两种独立的方法来量化海马神经发生。 已建立的小鼠 AD 模型 (3xTg AD) 中的静态 NSC 库 首先，我们将使用保留标签。 随着 AD 病理进展量化静态 NSC 库的实验 其次，我们将使用体内模型。 测定静止退出以测量沿同一时间线的 NSC 库的激活开始发现。 为了了解我们观察到的变化背后的机制，我们将在分离的 FACS 上进行单核 RNA 测序 小鼠 AD 模型中静态和激活的 NSC 的成功实现将提供这些目标。 对 AD 神经发生下降机制的新见解因此，我们预计这会发生。 研究将有助于发现治疗阿尔茨海默病和其他疾病的新治疗方法 神经退行性疾病。

项目成果

Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation.

干细胞表型可预测 MGMT 启动子甲基化的胶质母细胞瘤的治疗反应。

• 发表时间: 2022-11-04
• 影响因子: 7.1
• 作者: Lakis, Nelli S;Brodsky, Alexander S;Karashchuk, Galina;Audesse, Amanda J;Yang, Dongfang;Sturtevant, Ashlee;Lombardo, Kara;Wong, Ian Y;Webb, Ashley E;Anthony, Douglas C
• 通讯作者: Anthony, Douglas C

Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease.

衰老和阿尔茨海默病中的成人海马神经发生。

• 发表时间: 2021-04-13
• 影响因子: 5.9
• 作者: Babcock, Kelsey R;Page, John S;Fallon, Justin R;Webb, Ashley E
• 通讯作者: Webb, Ashley E

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

FOXO3 调节衰老干细胞和胶质母细胞瘤干细胞中的常见基因组程序。

• 发表时间: 2021-12
• 作者: Audesse, Amanda J;Karashchuk, Galina;Gardell, Zachary A;Lakis, Nelli S;Maybury;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.

神经干细胞衰老中增强静止的机制。

• 发表时间: 2020
• 影响因子: 5.3
• 作者: Audesse, Amanda J;Webb, Ashley E
• 通讯作者: Webb, Ashley E

FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis.

FoxO 功能对于维持成人神经发生中的自噬通量和神经元形态发生至关重要。

• 发表时间: 2018-09-19
• 影响因子: 16.2
• 作者: Schäffner, Iris;Minakaki, Georgia;Khan, M Amir;Balta, Elli;Schlötzer;Schwarz, Tobias J;Beckervordersandforth, Ruth;Winner, Beate;Webb, Ashley E;DePinho, Ronald A;Paik, Jihye;Wurst, Wolfgang;Klucken, Jochen;Lie, D Chich
• 通讯作者: Lie, D Chich