INPP5D/SHIP1 regulates endo-lysosome function and cargo-selective phagocytosis in human microglia

INPP5D, which encodes SHIP1, is genetically associated with Alzheimers disease (AD) risk and regulates microglial immune function. Here we identified SHIP1 as a regulator of endo-lysosomal homeostasis in human microglia. INPP5D haploinsufficiency impaired endosome maturation and lysosomal degradation, leading to lipid droplet accumulation, lysosomal stress, and NLRP3 inflammasome activation. SHIP1-deficient microglia shifted from an immune-responsive state toward a disease-associated state with elevated cargo-selective phagocytosis. Although amyloid-{beta} uptake was unaffected, SHIP1-deficient microglia accumulated intracellular amyloid-{beta} and exhibited exacerbated lipid droplet accumulation, consistent with defective lysosomal processing. Proteomic analysis of genetically diverse human microglia revealed that the protective INPP5D rs10933431 variant is associated with elevated phosphatase-domain containing SHIP1, and protein profiles consistent with enhanced endolysosomal trafficking. In mice xenografted with SHIP1-deficient human microglia, high amyloid-{beta} burden exacerbated lysosomal, lipid droplet and inflammasome phenotypes. Together, these findings identify disrupted endo-lysosomal trafficking and degradative capacity as mechanisms linking INPP5D dysfunction to disease-associated microglial states in AD.