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Updated: Jun 12, 2026
Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model
Published on: July 26, 2011
Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease
Emilie L Castranio1, Philip Hasel2, Jean-Vianney Haure-Mirande1
1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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.
Insights
Knocking down inositol polyphosphate-5-phosphatase D (INPP5D) in mice models of Alzheimer's disease increased amyloid plaque burden and microglia accumulation. This suggests INPP5D is a potential therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The inositol polyphosphate-5-phosphatase D (INPP5D) enzyme dephosphorylates phospholipids and phosphoproteins.
- Genetic variations in INPP5D are linked to an increased risk of late-onset sporadic Alzheimer's disease (LOAD).
Purpose of the Study:
- To investigate the functional role of INPP5D in Alzheimer's disease pathogenesis.
- To determine the consequences of inducible INPP5D knockdown in microglia of a mouse model for Alzheimer's disease.
Main Methods:
- Utilized a conditional knockout mouse model (PSAPP/Inpp5dfl/fl/Cx3cr1CreER/+) with inducible Inpp5d knockdown in microglia.
- Administered tamoxifen to induce recombination and Inpp5d knockdown.
- Analyzed amyloid plaque burden and microglia-associated changes at 6 months of age.
- Employed spatial transcriptomics to profile gene expression changes in response to Inpp5d knockdown.
Main Results:
- Inpp5d knockdown in microglia led to a significant increase in amyloid plaque deposition (6E10+ deposits).
- A higher percentage of microglia were associated with amyloid plaques in Inpp5d knockdown mice.
- Spatial transcriptomics revealed an altered plaque-specific gene expression profile, with cystatin F (CST7) identified as a novel plaque marker.
Conclusions:
- Conditional downregulation of INPP5D in microglia exacerbates Alzheimer's disease pathology in mice.
- Inpp5d plays a critical role in regulating microglial responses to amyloid plaques.
- The identified plaque-associated gene signature, altered by Inpp5d knockdown, shows overlap with human Alzheimer's disease gene networks, highlighting INPP5D as a potential therapeutic target.
