The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology

Introduction Mutations in INPP5D, which encodes for the SH2-domain-containing inositol phosphatase SHIP-1, have recently been linked to an increased risk of developing late-onset Alzheimer's disease. While INPP5D expression is almost exclusively restricted to microglia in the brain, little is known regarding how SHIP-1 affects neurobiology or neurodegenerative disease pathogenesis.Methods We generated and investigated 5xFAD Inpp5d(fl/fl)Cx3cr1(Ert2Cre) mice to ascertain the function of microglial SHIP-1 signaling in response to amyloid beta (Ab)-mediated pathology.Results SHIP-1 deletion in microglia led to substantially enhanced recruitment of microglia to Ab plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP-1 loss enhanced microglial plaque containment and Ab engulfment when compared to microglia from Cre-negative 5xFAD Inpp5d(fl/fl) littermate controls.Discussion These results define SHIP-1 as a pivotal regulator of microglial responses during Ab-driven neurological disease and suggest that targeting SHIP-1 may offer a promising strategy to treat Alzheimer's disease.

Automated summary

Mutations in the INPP5D gene have been associated with an increased risk of late-onset Alzheimer's disease. Deletion of SHIP-1 in microglia leads to improved neuronal health and enhanced clearance of amyloid beta plaques, suggesting that targeting SHIP-1 may be a promising strategy for treating Alzheimer's disease.