Cell autonomous and non-autonomous mechanisms in Alzheimer's disease and related dementias

阿尔茨海默病和相关痴呆的细胞自主和非自主机制

• 批准号: 10187414
• 负责人: Lisa M Ellerby
• 金额: $ 52.33万
• 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/10187414
• 关键词: 3xTg-AD mouse; Acute; Adopted; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Astrocytes; Brain; Cell Aging; Cell Communication; Cell Cycle Arrest; Cell model; Cells; Cerebrum; Coculture Techniques; Collaborations; Communication; Complement; Dasatinib; Dementia; Deposition; Development; Disease; Electrophysiology (science); Event; Excision; Goals; Hippocampus (Brain); Human; Huntington Disease; Impairment; Inflammation Mediators; Intervention; Lead; Mass Spectrum Analysis; Memory; Memory impairment; Microglia; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neuroglia; Neurons; Onset of illness; Organoids; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pharmaceutical Preparations; Phenotype; Physiology; Play; Post-Translational Protein Processing; Process; Quercetin; Role; Slice; Somatic Cell; Synapses; System; Systems Biology; Work; age related; age related neurodegeneration; aging brain; autocrine; behavioral phenotyping; cell type; density; human model; in vivo; induced pluripotent stem cell; mouse model; prevent; programs; response; senescence; single cell analysis; stem cell model; synaptic function; tau aggregation; tau phosphorylation; tau-1; therapeutic target; transcriptome sequencing; 3xTg-AD mouse; Acute; Adopted; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Astrocytes; Brain; Cell Aging; Cell Communication; Cell Cycle Arrest; Cell model; Cells; Cerebrum; Coculture Techniques; Collaborations; Communication; Complement; Dasatinib; Dementia; Deposition; Development; Disease; Electrophysiology (science); Event; Excision; Goals; Hippocampus (Brain); Human; Huntington Disease; Impairment; Inflammation Mediators; Intervention; Lead; Mass Spectrum Analysis; Memory; Memory impairment; Microglia; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neuroglia; Neurons; Onset of illness; Organoids; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pharmaceutical Preparations; Phenotype; Physiology; Play; Post-Translational Protein Processing; Process; Quercetin; Role; Slice; Somatic Cell; Synapses; System; Systems Biology; Work; age related; age related neurodegeneration; aging brain; autocrine; behavioral phenotyping; cell type; density; human model; in vivo; induced pluripotent stem cell; mouse model; prevent; programs; response; senescence; single cell analysis; stem cell model; synaptic function; tau aggregation; tau phosphorylation; tau-1; therapeutic target; transcriptome sequencing

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蜂窝衰老的原因和后果 与年龄相关的神经退行性的驱动器，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威尔 探索阿尔茨海默氏症细胞衰老的细胞自主和非自治机制 疾病（AD）和相关痴呆症。衰老的星形胶质细胞和神经元表现出类似衰老的变化 积聚在衰老的大脑中，我们假设这在AD中是一种原因。鼠标项目1的最新工作 帕金森氏症模型表明细胞衰老在PD病理学和进展中起着重要作用。 鼻孔剂（有选择地杀死衰老细胞的药物）支持AD中衰老的作用。 预防AD病理和行为表型。我们假设大脑中的神经元采用细胞 有助于AD的衰老样表型。我们将阐明大脑中的关键衰老细胞类型 他们与居住的单元格的通信，触发级联事件并导致小鼠和人类的广告 AD模型。神经元功能的年龄依赖性和衰老驱动损害及其对 将检查衰老的星形胶质细胞或小胶质细胞在AD的发作和进展中的作用。所以， 我们将检查蛋白质病诱导的神经元衰老及其对衰老胶质细胞的反应（星形胶质细胞 和小胶质细胞）。提出了以下特定目的：目标1。确定神经元如何变成senenscent 喜欢及其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小鼠模型中的病理和行为表型；目标3。模型细胞衰老表型 在AD的人体脑器官模型中。这些研究将加速衰老因素的发现 以及影响神经变性的下游目标，并使我们能够确定更好的治疗剂目标 AD和相关痴呆症。