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

INTRODUCTION: Gain-of-function 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 (LOAD). Yet, little is currently known in regards to how SHIP-1 affects neurobiology or neurodegenerative disease pathogenesis. METHODS: To bridge this knowledge gap, we generated 5xFAD Inpp5dfl/flCx3cr1Ert2Cre mice to investigate the function of microglial SHIP-1 signaling in response to amyloid beta (Aß)-mediated pathology. RESULTS: In our studies, we found that SHIP-1 deletion in microglia leads to substantially enhanced recruitment of microglia to Aß plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP-1 loss enhanced microglial plaque containment and Aß engulfment when compared to microglia from Cre-negative 5xFAD Inpp5dfl/fl littermate controls. DISCUSSION: These results define SHIP-1 as a pivotal regulator of microglial responses during Aß-driven neurological disease. Overall design: Flash-frozen corticies from 5xFAD Inpp5dfl/flCx3cr1ERT2Cre mice and 5xFAD littermate controls underwent nuclei extraction and single-nucleus RNA sequencing (snRNAseq).