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

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.

项目总结 该计划项目的目标是了解细胞衰老的原因和后果 年龄相关神经变性的驱动因素，确定衰老细胞驱动的新靶点和机制 并为改变疾病发生和/或进展的干预措施确定新的目标。项目3将 探索阿尔茨海默病细胞衰老的细胞自主和非自主机制 疾病(AD)和相关的痴呆症。衰老的星形胶质细胞和神经元呈现衰老性改变 在老化的大脑中积累，我们假设这是AD的原因。项目1中关于鼠标的最新工作 帕金森病的模型表明细胞衰老在帕金森病的病理和进展中起着重要作用。 衰老药物(选择性杀死衰老细胞的药物)的发现支持了衰老在AD中的作用。 预防AD病理和行为表型。我们假设大脑中的神经元采用一种细胞 导致阿尔茨海默病的衰老样表型。我们将阐明大脑中关键的衰老细胞类型和 它们与驻留细胞的通讯触发了一连串的事件，并导致了小鼠和人类的AD AD的模型。年龄依赖性和衰老驱动的神经元功能损害及其对 衰老的星形胶质细胞或小胶质细胞将被检测其在AD的发生和发展中的作用。因此， 我们将研究蛋白质病诱导的神经元衰老及其对衰老的胶质细胞(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.确定神经元如何变得有感觉 LIKE及其对衰老的星形胶质细胞或小胶质细胞的反应；目标2。确定细胞衰老是否驱动 阿尔茨海默病小鼠模型的病理和行为表型；以及目的3.模拟细胞衰老表型 在阿尔茨海默病的人脑器官模型中。这些研究将加速发现衰老因素 以及影响神经退化的下游靶点，使我们能够确定更好的治疗靶点 AD及相关痴呆症。