Alzheimer's disease (AD) is an intractable neurodegenerative disorder that devastates approximately 6.2 million Americans nationwide. Emerging evidence now establishes a central role for microglia in AD pathogenesis and reveals that transcriptional and epigenetic level changes in these cells tightly correlate with disease progression. Thus, targeting microglia with selective pharmacologic agents to control their cellular activity represents a powerful therapeutic avenue. However, precise microglia targeting requires broad knowledge of how the cell-surface proteome, or surfaceome, remodels in the disease environment, and this biology has not been systematically explored. I performed mass spectrometry-based surfaceome profiling of microglia after exposure to Aβ fibrils. My data revealed a robust upregulation of heparan sulfate proteoglycans and proteins that promote phagocytosis. In Aim 1 of this proposal, I will directly test if Aβ-induced heparan sulfate proteoglycans result in increased tau phagocytosis and seeding in human iPSC microglia. This hypothesis represents a unique framework that mechanistically links Aβ and tau pathology through microglia phagocytosis. In Aim 2, I will determine the tissue expression patterns of heparan sulfate proteoglycan in human AD brain. Finally, in Aim 3, I will engineer novel cell-surface degrading antibodies, called KineTACs, to specifically degrade disease-associated microglia targets from the cell-surface. The work outlined within this proposal is innovative and will greatly increase our understanding of microglia phagocytosis in AD and provide new recombinant tools to modulate this process. With the strong support of my scientific mentors and advisors at the University of California San Francisco, this K08 training proposal will enable me to cultivate mastery in iPSC cell culture models, human immunohistochemistry, and recombinant antibody engineering. This trajectory constitutes the first steps toward a broader career goal of becoming an independent physician-scientist studying the cellular and molecular mechanisms of neurodegeneration.