? Cellular senescence, astrocytes and Alzheimer's disease (Parent Grant: R01 AG051729, Cellular senescence as a mediator of mitochondrial dysfunction) Alzheimer's disease (AD) is a devastating neurodegenerative disease for which the largest single risk factor is age. At present, there are no efficacious treatments, and new approaches to understanding and managing the disease are desperately needed. AD research has focused largely on understanding how and why neurons lose function and ultimately die. A relatively understudied cell type, however, is the astrocyte, which is crucial for neuronal survival and function. Aging results in a progressive accumulation of astrocytes that have undergone cellular senescence ? a complex stress response that can radically alter cell function and, importantly, the ability of cells to interact and communicate with neighboring cells. Senescent cells increase with age in most mammalian tissues, including the brain, and many of their pathophysiological effects are thought to be a consequence of the complex senescence-associated secretory phenotype (SASP) -- the increased expression and secretion of numerous pro-inflammatory cytokines, chemokines, growth factors, proteases, bioactive lipids and damage-associated molecular patterns (DAMPs). Our preliminary data show a decline in the expression of genes that encode proteins responsible for the uptake of glutamate, an astrocytic function that is essential for preventing glutamate toxicity to neurons. We propose to explore this and other aspects of cellular senescence in astrocytes using state-of-the-art single cell sequencing techniques.
Our aim i s to understand in unprecedented depth the heterogeneity of the senescence responses of astrocytes, and to uncover vulnerabilities that have the potential to open new possibilities for interventions in AD.
? Cellular senescence, astrocytes and Alzheimer's disease (Parent Grant: R01 AG051729, Cellular senescence as a mediator of mitochondrial dysfunction) Alzheimer's disease (AD) is a devastating neurodegenerative disease for which the largest single risk factor is age. This supplemental request will explore a relatively understudied aspect of neuronal health and function: the role of astrocytes, an abundant cell in the brain that is crucial for neuronal survival. We will use state-of-the-art single cell sequencing to understand in unprecedented depth the heterogeneity of the senescence responses of astrocytes with the goal of uncovering new possibilities for intervention strategies in AD.
