Dataset Information

INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model.

ABSTRACT: The genetic associations of TREM2 loss-of-function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P₃ phosphatase expressed in microglia. In a Tyrobp-deficient TREM2 loss-of-function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aβ plaques, partially restored plaque compaction, and astrogliosis, and reduced phosphorylated tau⁺ dystrophic neurites. Mechanistic analyses suggest that TREM2/TYROBP and INPP5D exert opposing effects on PI(3,4,5)P₃ signaling pathways as well as on phosphoproteins involved in the actin assembly. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates Aβ-dependent pathological conversion of tau.

SUBMITTER: Iguchi A

PROVIDER: S-EPMC10074152 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model.

Iguchi Akihiro A Takatori Sho S Kimura Shingo S Muneto Hiroki H Wang Kai K Etani Hayato H Ito Genta G Sato Haruaki H Hori Yukiko Y Sasaki Junko J Saito Takashi T Saido Takaomi C TC Ikezu Tsuneya T Takai Toshiyuki T Sasaki Takehiko T Tomita Taisuke T

iScience 20230313 4

The genetic associations of TREM2 loss-of-function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, <i>INPP5D</i>, encoding ...[more]

PMID: 37035000

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Project description:Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ mouse models of Alzheimer disease likely hampers their translational potential. The novel App NL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for Aβ-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in App NL-G-F mice as a tool for therapy monitoring. Methods: App NL-G-F mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with 18F-florbetaben Aβ PET and 18F-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar Aβ and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous App NL-G-F mice had a rising SUV ratio in cortex and hippocampus for Aβ (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous App NL-G-F mice did not show significant changes with age. Significant voxelwise clusters of Aβ deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous App NL-G-F mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in App NL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in App NL-G-F treatment trials is poised to provide important insights in preclinical drug development.

Dataset Information

INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model.

Publications

INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model.

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