PROJECT SUMMARY The goals of the Program Project are to understand the causes and consequences of cellular senescence as a driver of age-related neurodegeneration, determine new targets and mechanisms by which senescent cells drive disease, and identify new targets for interventions that alter disease onset and/or progression. Project 3 will explore the cell-autonomous and non-autonomous mechanisms of cellular senescence in Alzheimer's disease (AD) and related dementia. Senescent astrocytes and neurons displaying senescent-like changes accumulate in the aging brain, and we hypothesize this is causative in AD. Recent work in Project 1 on mouse models of Parkinsonism suggests cellular senescence plays a significant role in PD pathology and progression. A role for senescence in AD is supported by the finding that senolytics (drugs that selectively kill senescent cells) prevent AD pathology and behavioral phenotypes. We hypothesize that neurons in the brain adopt a cellular senescent-like phenotype that contributes to AD. We will elucidate key senescent cell types in the brain and their communication with residing cells that trigger the cascade of events and lead to AD in mouse and human models of AD. Age-dependent and senescence-driven impairments of neuron function and their responses to senescent astrocytes or microglia will be examined for their roles in the onset and progression of AD. Therefore, we will examine proteinopathy-induced neuronal senescence and their response to senescent glia (astrocyte and microglia). The following Specific Aims are proposed: Aim 1. Determine how neurons become senenscent like and their response to senescent astrocytes or microglia; Aim 2. Determine if cellular senescence drives pathology and behavioral phenotypes in mouse models of AD; and Aim 3. Model cellular senescent phenotypes in human cerebral organoid models of AD. These studies will accelerate the discovery of senescence factors and downstream targets that influence neurodegeneration and allow us to identify better therapeutics targets for AD and related dementias.