High Resolution Profiling of Senescent Neurons and Their Microenvironments in Postmortem Human Brain Tissue Spanning Eight Decades of Life

跨八个十年生命的死后人脑组织中衰老神经元及其微环境的高分辨率分析

• 批准号: 10259700
• 负责人: Miranda Ethel Orr
• 金额: $ 38.76万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259700
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Americas; Apoptosis; Automobile Driving; Autopsy; Biological Aging; Biology of Aging; Brain; Brain Diseases; Cause of Death; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Differentiation process; Cell Nucleus; Cells; Cellular biology; Chronic; Chronology; Clinical; Color; Data; Dementia; Deposition; Disease; Disease Progression; Elderly; Environment; Functional disorder; Gene Expression; Germ Cells; Health; Histologic; Human; Inflammation; Intervention; Lasers; Life; Link; Longevity; Mediating; Mediator of activation protein; Methods; Mitotic; Molecular; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurosciences; Neurosciences Research; Oranges; Participant; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Pattern; Pharmacology; Phenotype; Population; Process; Research; Research Proposals; Resolution; Risk Factors; Role; Small Nuclear RNA; Source; Tauopathies; Testing; Tissues; Toxic effect; Transgenic Mice; Translating; Universities; Washington; biobank; biological adaptation to stress; brain health; brain tissue; cell injury; digital; effective therapy; entorhinal cortex; experimental study; laser capture microdissection; new therapeutic target; novel; novel therapeutics; protein expression; senescence; tau Proteins; tau aggregation; tissue degeneration; transcriptome sequencing; transcriptomics; treatment strategy

Project Summary/Abstract Advanced chronological age is the greatest risk factor for developing Alzheimer’s disease. Accumulating evidence suggests that disease processes may begin decades prior to dementia. Therefore, cellular and molecular processes that contribute to biological aging may also modulate Alzheimer’s disease pathogenesis. We recently identified a fundamental cellular aging stress response, cellular senescence, as a pathogenic process driving neurodegeneration in tauopathies, brain diseases histologically defined by tau protein accumulation. Features of cellular senescence include stable cell cycle arrest and toxic secretory phenotype. In this way, senescent cells escape cell death and become persistently deleterious to their surrounding environment. We have found a causal relationship connecting tau accumulation (i.e. neurofibrillary tangles), a neuronal senescence-like phenotype, and chronic neurodegeneration in tauopathies, including Alzheimer’s disease. As terminally differentiated cells, neurons may seem incapable of initiating a senescence stress response. However, our data indicate that neurons with mature neurofibrillary tangles are arrested in a cellular senescence-like state. The objective of this project is to identify the upstream molecular mediators and downstream cellular consequences of neuronal senescence in the human brain. High resolution profiling methods will be applied to analyze neurons across the adult human lifespan, and throughout the progressive stages of Alzheimer’s disease. This project will significantly advance the basic understanding of this novel neuronal cell fate, cellular senescence, and its influence on brain health. Moreover, the cellular and molecular pathways identified in our project may reveal novel therapeutic targets for intervention, and the age/stage of disease where they would be most beneficial.

项目概要/摘要 实际年龄较大是罹患阿尔茨海默病的最大危险因素。 有证据表明，疾病过程可能在痴呆症发生前几十年就开始了。 导致生物衰老的分子过程也可能调节阿尔茨海默病的发病机制。 我们最近发现了一种基本的细胞衰老应激反应，即细胞衰老，作为一种致病因素。 tau蛋白病、组织学上由tau蛋白定义的脑部疾病中驱动神经退行性变的过程 细胞衰老的特征包括稳定的细胞周期停滞和毒性分泌表型。 通过这种方式，衰老细胞逃脱了细胞死亡，并对其周围环境持续有害。 我们发现了 tau 蛋白积累（即神经原纤维缠结）之间的因果关系， 神经元衰老样表型，以及 tau 蛋白病（包括阿尔茨海默病）中的慢性神经变性 作为终末分化的细胞，神经元似乎无法引发衰老应激。 然而，我们的数据表明，具有成熟神经原纤维缠结的神经元被捕获。 该项目的目的是识别上游分子介质。 以及人脑神经元衰老的下游细胞后果的高分辨率分析。 方法将用于分析整个成年人生命周期以及整个渐进过程中的神经元 该项目将显着增进对这部小说的基本理解。 神经细胞命运、细胞衰老及其对大脑健康的影响。 我们项目中确定的途径可能会揭示新的干预治疗目标，以及年龄/阶段 疾病，他们将最有益。