Dissecting the impact of senescence on microglia function and neurodegeneration

剖析衰老对小胶质细胞功能和神经退行性变的影响

基本信息

批准号：
10043985
负责人：
Dorothy Patricia Schafer
金额：
$ 167.5万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043985
关键词：
APP-PS1 Acute Address Affect Age Aging Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Attenuated Biology Brain CDKN2A gene Cell Aging Cell Culture Techniques Cells Chronic DNA Damage Data Defect Deposition Disease Elderly Exhibits Functional disorder Genes Genetic Genetic Transcription Goals Homeostasis IL8 gene Image Immune Immunofluorescence Immunologic Impairment In Vitro Inflammation Inflammatory Injury Interleukin-1 beta Interleukin-6 Knock-in Mouse Lasers Learning Ligase Mediating Mediator of activation protein Memory Loss Metabolic Microglia Morphology Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Oncogenic Oxidative Stress Pathogenesis Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacotherapy Phenotype Positioning Attribute Process Protein Overexpression Regulation Risk Factors Role Senile Plaques Signal Transduction Stimulus Subfamily lentivirinae Synapses Synaptosomes Testing Therapeutic Intervention Tissues Translating Treatment outcome Work age related neurodegeneration aging brain astrocyte progenitor base beta-Galactosidase biological adaptation to stress cell type cytokine experimental study in vivo insight macrophage mouse model neural circuit neurodegenerative phenotype neuroinflammation neuroregulation novel novel therapeutics oligodendrocyte progenitor overexpression response risk variant senescence stem cells success tau Proteins telomere temporal measurement therapeutic target time use tool transcriptome sequencing transcriptomics two-photon ubiquitin-protein ligase uptake virtual

项目摘要

Project Summary/Abstract Cellular senescence is a general stress response that is triggered by many stimuli, including telomere dysfunction, DNA damage, oxidative stress, aberrant oncogenic signaling and chronic inflammation. Senescent cells cease proliferation, undergo metabolic and transcriptional changes and secrete various pro-inflammatory molecules, collectively known as senescence-associated secretory phenotype (SASP). SASP mediates many of the pathophysiological effects of senescence with advancing age in many tissues. Recent data in the brain suggest that glial cells become senescent during neurodegeneration. This includes microglia, a resident CNS macrophage. Importantly, ablating all senescent glial cells, including microglia, astrocytes, and oligodendrocyte progenitor cells, is neuroprotective in mouse models of Alzheimer’s disease (AD)-related and tau-dependent neurodegeneration. However, it is unknown how senescence impacts microglial function and how senescent microglia then contribute to the disease process. A common feature among neurodegenerative diseases are reactive, pro-inflammatory microglia with dysfunctional phagocytic function, we will now test the hypothesis that senescence inhibits normal microglial phagocytic function and promotes a pro-inflammatory cell type, which accelerates AD-relevant neurodegeneration. We will test this hypothesis using a senescence regulator Smurf2 as a genetic tool. Using cell culture or mice with conditional overexpression of Smurf2, we have the unique capability to induce senescence specifically in microglia with high temporal resolution in vitro and in vivo. We also can express a ligase-dead Smurf2 as an elegant control for protein overexpression. Using these tools, we will investigate whether senescence in microglia affects their ability to phagocyte synapses and amyloid Aβ in Aim 1. In Aim 2, we will assess how senescence affects microglial homeostasis and transition into a reactive, pro-inflammatory state. In Aim 3, we will determine the impact of senescent microglia on neurodegenerative phenotypes in the APP/PS1 model of AD-relevant neurodegeneration and identify whether senolytic treatment to ablate senescent cells can attenuate or reverse neurodegeneration. These aims are supported by our strong preliminary data that we can overexpress Smurf2 and induce senescence in microglia in vitro and in vivo . Further, in vitro senescent microglia exhibit reduced phagocytosis of cellular debris, reminiscent of what is observed in AD and engulfment of Aβ. Leveraging our unique genetic tool kit and our combined expertise in microglial biology (Schafer) and senescence mechanisms (Zhang), we are in a strong position to gain fundamental insight into how cellular senescence affects microglial function and, in turn, the neurodegenerative process. Long-term, we aim to identify novel, senescence-based therapeutic targets for AD and other related diseases where aging is a major risk factor.

项目摘要/摘要细胞感应是一种一般应力反应，由许多刺激触发，包括端粒功能障碍，DNA损伤，氧化应激，异常的致癌信号传导和慢性炎症。衰老细胞停止增殖，发生代谢和转录变化以及秘密各种促炎分子，统称为感应相关的秘书表型（SASP）。 SASP培养了许多感应的病理生理影响随着许多组织的年龄增长。大脑中的最新数据表明神经胶质细胞在神经退行性过程中变得有感觉。这包括小胶质细胞，居民中枢神经系统巨噬细胞。重要的是，消除所有感觉神经胶质细胞，包括小胶质细胞，星形胶质细胞和少突胶质细胞祖细胞在阿尔茨海默氏病小鼠模型（AD）相关的小鼠模型中具有神经保护作用神经变性。然而，尚不清楚感应如何影响小胶质细胞功能以及如何感应然后，小胶质细胞有助于疾病过程。神经退行性疾病中的一个共同特征是反应性，促炎性小胶质细胞具有功能失调的吞噬功能，我们现在将检验以下假设。感应抑制正常的小胶质细胞功能，并促进促炎细胞类型，该细胞类型加速与广告相关的神经变性。我们将使用sensctun调节器Smurf2检验该假设作为遗传工具。使用细胞培养物或小鼠与Smurf2的条件过表达，我们具有独特的能够在体外和体内高临时分辨率的小胶质细胞中特别诱导感应。我们还可以表达连接酶已故的蓝精子作为蛋白质过表达的优雅控制。使用这些工具，我们将研究小胶质细胞中的感应是否影响其吞噬突触的能力和淀粉样蛋白Aβ在 AIM 1。在AIM 2中，我们将评估感应如何影响小胶质体稳态并过渡为反应性，促炎性状态。在AIM 3中，我们将确定感觉小胶质细胞对神经退行性的影响 APP/PS1与AD相关神经变性的模型中的表型，并确定鼻溶剂是否治疗灌溉感觉细胞可以减弱或逆转神经变性。这些目标得到了我们强大的支持初步数据，我们可以过表达smurf2并在体外和体内诱导小胶质细胞感染。此外，体外感觉小胶质细胞暴露于细胞碎片的吞噬作用减少，提醒什么是在Aβ的AD和吞噬中观察到。利用我们独特的遗传工具套件和我们的联合专业知识小胶质细胞生物学（Schafer）和感应机制（Zhang），我们处于强大的位置对细胞感应如何影响小胶质功能的基本见解，然后神经退行性过程。长期，我们旨在确定新颖的，基于感应的治疗靶标的衰老是主要危险因素的AD和其他相关疾病。