Project Summary Age is the main risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder rapidly increasing in both incidence and prevalence as the population becomes older. Unfortunately, AD is the only top ten cause of death with no effective treatments. Therefore, the development of disease-altering treatments for AD is an urgent and unmet need. Although the exact etiology of AD is unknown, microglia, the tissue-resident macrophages of the brain, have been implicated in disease pathogenesis based on the observation that genetic variants in several microglia-specific genes significantly alter disease risk. In the healthy brain, microglia maintain homeostasis through multiple modalities including phagocytic clearance of pathogens, apoptotic cells, and debris. In AD brains and age-matched clinically-unimpaired brains alike, microglia are dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired phagocytic degradation of debris. These findings suggest that the general decline in phagocytosis with age might underlie pathological neurodegeneration. However, the mechanisms of age-related microglial dysfunction are poorly understood. This proposal aims to elucidate the mechanisms of impaired microglial phagocytosis in the aging brain and to uncover therapeutic strategies to reverse this impairment in AD. Preliminary data suggest that cell-surface sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia. Aim 1 combines biochemical and genetic tools to identify upstream and downstream signaling partners that transduce the anti- phagocytic effect of sialic acid on aged microglia. Aim 2 will evaluate the therapeutic potential of blocking the interaction between cell-surface sialic acid and its cognate receptor on microglia to promote phagocytosis and ameliorate cognitive decline in a mouse model of AD. These experiments will elucidate a mechanism of microglial dysfunction during normal aging with direct translational implications for patients with AD.