Cellular senescence and cell fate/interactions as drivers of Alzheimer's and age-related dementias

细胞衰老和细胞命运/相互作用是阿尔茨海默氏症和年龄相关性痴呆的驱动因素

• 批准号: 10709275
• 负责人: Judith Campisi
• 金额: $ 4.65万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709275
• 关键词: Acceleration; Adopted; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Astrocytes; Brain; Cell Aging; Cell model; Cells; Cerebrum; Communication; Dementia; Development; Disease; Disease Progression; Event; Goals; Human; Impairment; Intervention; Microglia; Nerve Degeneration; Neuroglia; Neurons; Onset of illness; Organoids; Parkinsonian Disorders; Pathology; Pharmaceutical Preparations; Phenotype; Play; Risk Factors; Role; Work; age related; age related neurodegeneration; aging brain; behavioral phenotyping; brain cell; cell type; effective intervention; human model; insight; mouse model; prevent; programs; response; senescence; therapeutic target

PROJECT SUMMARY The goals of the Program Project are to understand the causes and consequences of cellular senescence as a driver of age-related neurodegeneration, determine new targets and mechanisms by which senescent cells drive disease, and identify new targets for interventions that alter disease onset and/or progression. Project 3 will explore the cell-autonomous and non-autonomous mechanisms of cellular senescence in Alzheimer's disease (AD) and related dementia. Senescent astrocytes and neurons displaying senescent-like changes accumulate in the aging brain, and we hypothesize this is causative in AD. Recent work in Project 1 on mouse models of Parkinsonism suggests cellular senescence plays a significant role in PD pathology and progression. A role for senescence in AD is supported by the finding that senolytics (drugs that selectively kill senescent cells) prevent AD pathology and behavioral phenotypes. We hypothesize that neurons in the brain adopt a cellular senescent-like phenotype that contributes to AD. We will elucidate key senescent cell types in the brain and their communication with residing cells that trigger the cascade of events and lead to AD in mouse and human models of AD. Age-dependent and senescence-driven impairments of neuron function and their responses to senescent astrocytes or microglia will be examined for their roles in the onset and progression of AD. Therefore, we will examine proteinopathy-induced neuronal senescence and their response to senescent glia (astrocyte and microglia). The following Specific Aims are proposed: Aim 1. Determine how neurons become senenscent like and their response to senescent astrocytes or microglia; Aim 2. Determine if cellular senescence drives pathology and behavioral phenotypes in mouse models of AD; and Aim 3. Model cellular senescent phenotypes in human cerebral organoid models of AD. These studies will accelerate the discovery of senescence factors and downstream targets that influence neurodegeneration and allow us to identify better therapeutics targets for AD and related dementias.

项目摘要 该计划项目的目标是了解细胞衰老的原因和后果， 年龄相关性神经退行性变的驱动因素，确定衰老细胞驱动的新目标和机制， 疾病，并确定改变疾病发作和/或进展的干预措施的新目标。项目3将 探索阿尔茨海默氏症细胞衰老的细胞自主和非自主机制 疾病（AD）和相关痴呆。衰老的星形胶质细胞和神经元呈现衰老样改变 在老化的大脑中积累，我们假设这是AD的病因。最近在Project 1上的工作 帕金森综合征模型表明细胞衰老在PD病理和进展中起重要作用。 衰老在AD中的作用得到了以下发现的支持：衰老抑制剂（选择性杀死衰老细胞的药物） 预防AD病理和行为表型。我们假设大脑中的神经元采用了一种 导致AD的衰老样表型。我们将阐明大脑中关键的衰老细胞类型， 它们与驻留细胞的通信触发级联事件并导致小鼠和人类的AD AD模型神经元功能的依赖性和衰老驱动的损伤及其对 将检查衰老的星形胶质细胞或小胶质细胞在AD发病和进展中的作用。因此，我们认为， 我们将研究蛋白质病诱导的神经元衰老及其对衰老胶质细胞（星形胶质细胞）的反应 和小胶质细胞）。提出了以下具体目标：目标1。确定神经元如何衰老 以及它们对衰老星形胶质细胞或小胶质细胞的反应; Aim 2.确定细胞衰老是否驱动 AD小鼠模型中的病理学和行为表型;以及目的3.模型细胞衰老表型 在AD的人脑类器官模型中。这些研究将加速衰老因子的发现 以及影响神经退行性变的下游靶点，使我们能够确定更好的治疗靶点， AD和相关痴呆。