INPP5D encodes SHIP1, a lipid phosphatase that hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating PI3K signaling pathways 1. In the immune system, SHIP1 acts as a negative regulator of B-cell antigen receptor signaling and mediates signaling from Fc-gamma-RIIB receptors, playing a central role in terminating immune cell activation 2. In the brain, INPP5D functions as a critical regulator of microglial activity. SHIP1 limits complement-mediated synaptic pruning during healthy brain development, with SHIP1-deficient microglia showing increased complement activation and excessive synapse loss 3. The protein serves as a negative regulator of the NLRP3 inflammasome in human microglia, with reduced INPP5D activity leading to inflammasome activation and increased IL-1β and IL-18 secretion 4. INPP5D is genetically associated with Alzheimer's disease risk, and its expression is increased in AD brains 5. In AD pathogenesis, microglial APOE4 induces TGFβ signaling that upregulates INPP5D, impairing the neuroprotective microglial response and facilitating disease progression 6. These findings position INPP5D as a key regulator of microglial function with significant implications for neurodegeneration and immune regulation.