The SHIP1-inflammatory-lipid axis in Alzheimer’s disease: from genetic risk to spatiotemporal mechanistic insights

The INPP5D gene, encoding the SHIP1 protein, has been identified as a prominent genetic risk factor for Alzheimer’s disease (AD). However, its multifunctional roles remain complex. SHIP1 serves as a pivotal integrative node linking microglial immune activation with lipid metabolism. This review synthesizes current evidence on the SHIP1-inflammatory-lipid axis, elucidating how its phosphatase and scaffold functions modulate microglial homeostasis through the PI3K-Akt signaling pathway and the NLRP3 inflammasome. We propose a novel lipid‒lysosome‒inflammation cycle model in which SHIP1 deficiency initiates a self-perpetuating cascade of lipid sequestration and lysosomal impairment that fuels chronic inflammatory priming. Furthermore, we propose a stage-dependent duality of SHIP1, characterized by its transition from a beneficial homeostatic brake in early disease to a pathological checkpoint that hinders essential metabolic and phagocytic adaptation in advanced stages. This dysregulation leads to widespread multicellular network disruption across neurons and the neurovascular unit. Finally, we evaluate current pharmacological strategies and advocate for the precise spatiotemporal modulation of SHIP1 activity to disrupt the converging pathological axes and facilitate next-generation therapies for Alzheimer’s disease.