Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease
Year: 2021
Type: article
Abstract: Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.
Institutions: Research Institute of Environmental Medicine, Nagoya University, Nagoya University, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Institute of Gerontology, Tokyo Metropolitan Geriatric Hospital, The University of Osaka, Nagoya City University, RIKEN Center for Brain Science, National Institutes for Quantum Science and Technology, National Institute of Radiological Sciences, Institute for Radiological Science
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,170
Awards: G2551808474, Investigating mechanisms of tau-induced neurotxicity, G4576190013, 神経炎症制御を標的としたアルツハイマー病の治療薬シーズ探索, Elucidating the molecular mechanism and therapeutic targets of glial activity in Alzheimer's diseasea, G6373681111, 老化・認知症拠点の構築, Platform of Supporting Cohort Study and Biospecimen Analysis, Disruption of the mitochondria-associated membranes as a general pathomechanism in amyotrophic lateral sclerosis, G8727386421
OpenAlex ID: W3119403831