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Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease.
- Source :
-
Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2023 Jun; Vol. 19 (6), pp. 2239-2252. Date of Electronic Publication: 2022 Nov 30. - Publication Year :
- 2023
-
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).<br />Methods: To assess the consequences of inducible Inpp5d knockdown in microglia of APP <superscript>KM670/671NL</superscript> /PSEN1 <superscript>Δexon9</superscript> (PSAPP) mice, we injected 3-month-old Inpp5d <superscript>fl/fl</superscript> /Cx3cr1 <superscript>CreER/+</superscript> and PSAPP/Inpp5d <superscript>fl/fl</superscript> /Cx3cr1 <superscript>CreER/+</superscript> mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination.<br />Results: At age 6 months, we found that the percent area of 6E10 <superscript>+</superscript> 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.<br />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.<br />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.<br /> (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
- Subjects :
- Mice
Humans
Animals
Infant
Microglia metabolism
Mice, Transgenic
Plaque, Amyloid metabolism
Disease Models, Animal
Amyloid beta-Peptides metabolism
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases genetics
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases metabolism
Alzheimer Disease genetics
Alzheimer Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1552-5279
- Volume :
- 19
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Alzheimer's & dementia : the journal of the Alzheimer's Association
- Publication Type :
- Academic Journal
- Accession number :
- 36448627
- Full Text :
- https://doi.org/10.1002/alz.12821