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Introduction The inositol polyphosphate‐5‐phosphatase D (INPP5D) gene encodes a dual‐specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimer's disease (LOAD). Methods To assess the consequences of inducible Inpp5d knockdown in microglia of APPKM670/671NL/PSEN1Δexon9 (PSAPP) mice, we injected 3‐month‐old Inpp5dfl/fl/Cx3cr1CreER/+ and PSAPP/Inpp5dfl/fl/Cx3cr1CreER/+ mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination. Results At age 6 months, we found that the percent area of 6E10+ deposits and plaque‐associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque‐specific expression profile that was extensively altered by Inpp5d knockdown. Discussion These results demonstrate that conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques. Spatial transcriptomics highlighted an extended gene expression signature associated with plaques and identified CST7 (cystatin F) as a novel marker of plaques. Highlights Inpp5d knockdown increases plaque burden and plaque‐associated microglia number. Spatial transcriptomics identifies an expanded plaque‐specific gene expression profile. Plaque‐induced gene expression is altered by Inpp5d knockdown in microglia. Our plaque‐associated gene signature overlaps with human Alzheimer's disease gene networks.

The dual specificity lipid/protein phosphatase SHIP1 (encoded by the INPP5D gene) is enriched in myeloid cells. Single nucleotide polymorphisms (SNPs) in INPP5D coding and non-coding regions impact risk for developing late onset sporadic Alzheimer’s disease (LOAD). We present pathological analyses with spatial transcriptomics of mice with tamoxifen-sensitive microglial knockdown of Inpp5d and show exacerbated plaque pathology, plaque-associated microglial density, and altered gene expression around plaques, suggesting novel markers for plaque-associated reactive microglia.

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