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

项目摘要/摘要 高龄是罹患阿尔茨海默病的最大风险因素。积累 有证据表明，疾病过程可能在痴呆症之前几十年就开始了。因此，蜂窝和 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，是一种致病因素 在tau病中驱动神经变性的过程，即由tau蛋白组织学定义的脑部疾病 积累。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，衰老的细胞逃脱了细胞死亡，并对周围环境持续有害。 环境。我们已经发现了tau堆积(即神经纤维缠结)之间的因果关系， 包括阿尔茨海默氏病在内的神经元性疾病中的神经元衰老样表型和慢性神经变性 疾病。作为终末分化的细胞，神经元似乎不能启动衰老压力。 回应。然而，我们的数据表明，具有成熟神经原纤维缠结的神经元在 细胞类衰老状态。本项目的目标是确定上游分子介体。 以及人类大脑中神经元衰老的下游细胞后果。高分辨率剖面法 这些方法将被应用于分析成年人类寿命和整个进展期的神经元。 阿尔茨海默氏症的各个阶段。这个项目将极大地促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。此外，细胞和分子 在我们的项目中确定的通路可能揭示新的干预治疗靶点，以及 疾病，他们将是最有益的。

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.