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: 10414099
• 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/10414099
• 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.

项目摘要/摘要 晚期年龄是发展阿尔茨海默氏病的最大危险因素。累积 有证据表明，疾病过程可能在痴呆之前开始。因此，细胞和 有助于生物衰老的分子过程也可能调节阿尔茨海默氏病的发病机理。 我们最近确定了基本的细胞衰老应力反应，细胞感应为致病性 tau蛋白定义的脑部疾病的过程驱动神经退行性的脑部疾病 积累。细胞感应的特征包括稳定的细胞周期停滞和有毒的秘密表型。 这样，感觉细胞逃脱了细胞死亡，并持续删除到周围 环境。我们发现了连接tau积累（即神经纤维缠结）的因果关系， 在包中的神经元感应表型和慢性神经变性，包括阿尔茨海默氏症 疾病。由于终端分化的细胞，神经元似乎无法引发感应应力 回复。但是，我们的数据表明具有成熟神经原纤维缠结的神经元被捕 细胞感应状态。该项目的目的是确定上游分子介体 人脑中神经元感应的下游细胞后果。高分辨率分析 方法将用于分析成人人类寿命的神经元，以及整个渐进性 阿尔茨海默氏病的阶段。这个项目将大大提高对这部小说的基本理解 神经元细胞命运，细胞感应及其对脑健康的影响。此外，细胞和分子 我们项目中确定的途径可能揭示了干预的新型治疗靶标，以及年龄/阶段 它们将是最有益的疾病。