Investigating the Role of Adipose Senescent Cells in Cognitive Function and Alzheimer's Disease Progression

Investigating the Role of Adipose Senescent Cells in Cognitive Function and Alzheimer's Disease Progression Abstract Alzheimer's disease (AD) is an incurable neurodegenerative disorder that poses extensive challenges to patients, families, and healthcare systems. Existing treatments are limited by an insufficient understanding of the basic biology underlying disease development. The most prominent risk factor for dementia and AD is aging and obesity, suggesting that chronic conditions may represent significant contributors to AD pathogenesis. Cellular senescence, a cellular state characterized by permanent cell cycle arrest, is induced by external stressors. Senescent cells produce various bioactive molecules, known as senescence-associated secretory phenotype (SASP) factors, which can influence the local tissue microenvironment and promote systemic inflammation. SASP factors can have far-reaching impacts, with endocrine-like systemic effects, and reducing senescent cell accumulation has been found to have beneficial effects, leading researchers to further explore the roles played by senescent cells in age-related disease pathogenesis. Preliminary studies suggest a potential link between the accumulation of senescent cells in adipose tissue and brain dysfunction, implying that senescent cells in adipose tissue may contribute to cognitive decline and neurodegeneration via endocrine effects. We hypothesize that the aging- or obesity-driven accumulation of adipose senescent cells contributes to cognitive deficits and neurodegeneration, including AD-related dysfunction, through endocrine effects. We propose to determine the potential roles played by adipose SnCs on microglial senescence, potentially contributing to cognitive decline and Alzheimer's progression, in mouse models of aging, obesity, and AD. Our novel Adipoq-INK-ATTAC mouse model will enable the targeted depletion of senescent cells from adipose tissue to further assess the roles played by these cells in aging, obesity, and AD pathology. These investigations will allow us to ascertain whether peripheral senescent cells represent potential novel therapeutic targets for neurodegenerative disorders, particularly AD, aiding the development of future intervention strategies.