Dataset Information

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

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 APP^KM670/671NL /PSEN1^Δexon9 (PSAPP) mice, we injected 3-month-old Inpp5d^fl/fl /Cx3cr1^CreER/+ and PSAPP/Inpp5d^fl/fl /Cx3cr1^CreER/+ 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.

SUBMITTER: Castranio EL

PROVIDER: S-EPMC10481344 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Castranio Emilie L EL Hasel Philip P Haure-Mirande Jean-Vianney JV Ramirez Jimenez Angie V AV Hamilton B Wade BW Kim Rachel D RD Glabe Charles G CG Wang Minghui M Wang Minghui M Zhang Bin B Gandy Sam S Liddelow Shane A SA Ehrlich Michelle E ME

Alzheimer's & dementia : the journal of the Alzheimer's Association 20221130 6

<h4>Introduction</h4>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).<h4>Methods</h4>To assess the consequences of inducible Inpp5d knockdown in microglia of APP<sup>KM670/671NL</sup> /PSEN1<sup>Δexon9</sup> (PSAPP) mice, we injected 3-month-old Inpp5d<sup>fl/fl</sup> /C ...[more]

PMID: 36448627

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Project description:IntroductionAlzheimer's disease (AD) is characterized by increasing cognitive dysfunction, progressive cerebral amyloid beta (Aβ) deposition, and neurofibrillary tangle aggregation. However, the molecular mechanisms of AD pathologies have not been completely understood. As synaptic glycoprotein neuroplastin 65 (NP65) is related with synaptic plasticity and complex molecular events underlying learning and memory, we hypothesized that NP65 would be involved in cognitive dysfunction and Aβ plaque formation of AD. For this purpose, we examined the role of NP65 in the transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD.MethodsNeuroplastin 65-knockout (NP65-/-) mice crossed with APP/PS1 mice to get the NP65-deficient APP/PS1 mice. In the present study, a separate cohort of NP65-deficient APP/PS1 mice were used. First, the cognitive behaviors of NP65-deficient APP/PS1 mice were assessed. Then, Aβ plaque burden and Aβ levels in NP65-deficient APP/PS1 mice were measured by immunostaining and western blot as well as ELISA. Thirdly, immunostaining and western blot were used to evaluate the glial response and neuroinflammation. Finally, protein levels of 5-hydroxytryptamin (serotonin) receptor 3A and synaptic proteins and neurons were measured.ResultsWe found that loss of NP65 alleviated the cognitive deficits of APP/PS1 mice. In addition, Aβ plaque burden and Aβ levels were significantly reduced in NP65-deficient APP/PS1 mice compared with control animals. NP65-loss in APP/PS1 mice resulted in a decrease in glial activation and the levels of pro- and anti-inflammatory cytokines (IL-1β, TNF-α, and IL-4) as well as protective matrix YM-1 and Arg-1, but had no effect on microglial phenotype. Moreover, NP65 deficiency significantly reversed the increase in 5-hydroxytryptamine (serotonin) receptor 3A (Htr3A) expression levels in the hippocampus of APP/PS1 mice.DiscussionThese findings identify a previously unrecognized role of NP65 in cognitive deficits and Aβ formation of APP/PS1 mice, and suggest that NP65 may serve as a potential therapeutic target for AD.

Dataset Information

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

Introduction

Methods

Results

Discussion

Highlights

Publications

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

Similar Datasets

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