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.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia, neuropathologically characterized by the accumulation of amyloid β (Aβ), phosphorylated Tau, and neuronalSobue et al acta neuropathol commun (2021) 9:1 the proinflammatory “classical” activation phenotype (M1) and the anti-inflammatory “alternative” activated phenotype (M2) [44]
We analyzed gene expression in microglia isolated by magnetic-activated cell sorting (MACS) from cerebral cortex of AppNL-G-F/NL-G-F and rTg4510 mice or lumbar spinal cord of SOD1G93A mice at the middle-to-late disease stage (Fig. 1a, b)
Upregulation of ApoE was limited in plaque-associated microglia of AppNL-G-F/NL-G-F mice, immunoreactivity of ApoE was increased in microglia of all three models (Fig. 3e–g). These results suggest that neurodegenerative diseases have upregulation of most disease-associated microglia (DAM) genes in common, but levels of expression were not correlated with the degree of neuronal cell loss
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia, neuropathologically characterized by the accumulation of amyloid β (Aβ), phosphorylated Tau, and neuronalSobue et al acta neuropathol commun (2021) 9:1 the proinflammatory “classical” activation phenotype (M1) and the anti-inflammatory “alternative” activated phenotype (M2) [44]. Recent studies demonstrated that a common disease-associated microglia (DAM) or “neurodegenerative” phenotype, defined by a small set of upregulated genes, was observed in neurodegenerative diseases including AD, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia, and aging [10, 20, 24]. It remains unclear whether the loss of homeostatic function in microglia or the DAM phenotype is correlated with the degree of neuronal cell loss, and whether DAM is beneficial or detrimental to neurodegenerative diseases.
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