Cellular senescence in Alzheimer's disease

With increasing age, cells that have accumulated molecular damage leading to a cellular senescence/proinflammatory senescence-associated secretory phenotype (SASP) accumulate to different degrees in tissue cell populations, creating a proinflammatory environment that results in compromised tissue function. In the brain, some cell populations (e.g. neurons) become post-mitotic early in life, while others (e.g. glia), preserve the capacity for cell division and for bona fide senescence.  Indeed, senescent astrocytes and neurons displaying senescent-like changes accumulate in the aging brain, and emerging evidence indicates that Alzheimer’s patients have significantly more senescent astrocytes in frontal cortex than similarly aged non-AD control subjects. The importance of cellular senescence in the etiology of various age-associated diseases was recently recognized, but its role in AD is presently not known.  Cellular senescence and the SASP are potently blocked by attenuation of the target of rapamycin (TOR), and our studies indicate that mTOR regulates cellular senescence/SASP in vivo. The goal of this project is to determine the role of systemic and brain cellular senescence in the pathogenesis of histopathologic and functional deficits of AD in surrogate models, and to explore cell type-specific mechanisms involved.