The Alzheimer's disease risk factor <i>INPP5D</i> restricts neuroprotective microglial responses in amyloid beta‐mediated pathology
Joshua D. Samuels, Katelyn A. Moore, Hannah Ennerfelt, Alexis M. Johnson, Adeline E. Walsh, Richard J. Price, John R. Lukens
Abstract
Abstract 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 (Aβ)‐mediated pathology. Results SHIP‐1 deletion in microglia led to substantially enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP‐1 loss enhanced microglial plaque containment and Aβ 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 Aβ‐driven neurological disease and suggest that targeting SHIP‐1 may offer a promising strategy to treat Alzheimer's disease. Highlights Inpp5d deficiency in microglia increases plaque‐associated microglia numbers. Loss of Inpp5d induces activation and phagocytosis transcriptional pathways. Plaque encapsulation and engulfment by microglia are enhanced with Inpp5d deletion. Genetic ablation of Inpp5d protects against plaque‐induced neuronal dystrophy.