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

项目总结/摘要 老年痴呆症是老年痴呆症的最大危险因素。积累 有证据表明，疾病过程可能在痴呆症之前开始几十年就开始了。因此，细胞和 导致生物老化的分子过程也可能调节阿尔茨海默病的发病机制。 我们最近确定了一个基本的细胞衰老应激反应，细胞衰老，作为一种致病性的 在tau蛋白病、由tau蛋白组织学定义的脑疾病中驱动神经变性的过程 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，衰老细胞逃避细胞死亡并对其周围环境持续有害。 环境我们已经发现了连接tau积累（即神经元缠结）的因果关系， 神经元衰老样表型，以及包括阿尔茨海默病在内的tau蛋白病中的慢性神经变性 疾病作为终末分化的细胞，神经元似乎不能启动衰老应激 反应然而，我们的数据表明，具有成熟神经元缠结的神经元在一个特定的时间内被阻滞， 细胞衰老样状态。本项目的目的是鉴定上游分子介导物 以及人脑中神经元衰老的下游细胞后果。高分辨率剖面 方法将被应用于分析神经元在整个成年人的生命，并在整个渐进的 老年痴呆症的症状这个项目将大大推进对这部小说的基本理解 神经元细胞命运、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途径可能揭示新的治疗目标的干预，和年龄/阶段的 疾病，这将是最有益的。

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.