Dataset Information

T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis.

ABSTRACT: Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8⁺ T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.

SUBMITTER: Kedia S

PROVIDER: S-EPMC11303250 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis.

Kedia Shreeya S Ji Hao H Feng Ruoqing R Androvic Peter P Spieth Lena L Liu Lu L Franz Jonas J Zdiarstek Hanna H Anderson Katrin Perez KP Kaboglu Cem C Liu Qian Q Mattugini Nicola N Cherif Fatma F Prtvar Danilo D Cantuti-Castelvetri Ludovico L Liesz Arthur A Schifferer Martina M Stadelmann Christine C Tahirovic Sabina S Gokce Ozgun O Simons Mikael M

Nature neuroscience 20240627 8

Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer's disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer's disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8<sup>+</sup> T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses a ...[more]

PMID: 38937583

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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

T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis.

Publications

T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis.

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