INPP5D/SHIP1 in Alzheimer’s Disease: Linking Microglial Substrate Handling to Neuroinflammation and Neurovascular Dysfunction

INPP5D, which encodes Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), has emerged as an Alzheimer’s disease (AD)-associated gene with strong links to microglial biology. As a hematopoietic-enriched lipid phosphatase, SHIP1 converts phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-3,4-bisphosphate, thereby regulating phosphoinositide-dependent receptor signaling, membrane remodeling, phagocytosis, vesicle trafficking, and inflammatory responses. In AD, microglia are chronically exposed to amyloid-β, lipid-rich debris, damaged synapses, complement-tagged structures, and inflammatory mediators. These substrates require coordinated uptake, endolysosomal processing, autophagic adaptation, and controlled inflammatory output. Current data place INPP5D/SHIP1 at a step after receptor engagement, where microglial uptake must be coupled to vesicular routing and lysosomal degradation. When this coupling fails, engulfed amyloid, lipid debris, or synaptic material may accumulate in stressed endolysosomal compartments, promoting defective autophagy, NLRP3 inflammasome activation, and sustained cytokine release. Although current data support a primarily microglial or myeloid-centered role for INPP5D in the brain, altered microglial states may secondarily affect the neurovascular unit through cytokine release, complement activation, oxidative stress, and impaired amyloid or lipid clearance. This review summarizes the molecular function of INPP5D/SHIP1 in AD-related microglial signaling and discusses its implications for phagocytosis, endolysosomal stress, inflammasome activation, therapeutic targeting, and microglia–vascular communication.