Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease

Emilie L. Castranio, Philip Hasel, Jean Vianney Haure-Mirande, Angie V. Ramirez Jimenez, B. Wade Hamilton, Rachel D. Kim, Charles G. Glabe, Minghui Wang, Bin Zhang, Sam Gandy, Shane A. Liddelow, Michelle E. Ehrlich

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2239-2252
Number of pages14
JournalAlzheimer's and Dementia
Volume19
Issue number6
DOIs
StatePublished - Jun 2023

Keywords

  • Alzheimer's disease
  • Inpp5d
  • SHIP1
  • cystatin F
  • microglia
  • oligomer
  • spatial transcriptomics

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