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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.