In vivo mouse microglia scRNA seq
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE245391 | GEO | 2023/10/20
REPOSITORIES: GEO
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Project description:γ-Secretase is involved in the regulated intramembrane proteolysis (RIP) of a variety of integral membrane proteins and generates the amyloid peptide (Aβ) in Alzheimer’s Disease (AD). Microglia are centrally involved in AD, but the substrates and function of γ-secretase in these cells remain largely unstudied. Using a novel γ-Secretase Substrate Identification (G-SECSI) method, we identified 85 substrates, of which 59 were previously unknown, in stem cell derived microglia-like cells. More than 60% of those are signalling receptors possibly involved in cell state regulation. Inhibition of γ-secretase using Semagacestat or selective genetic knockout alters the expression of homeostatic (HM) and disease-associated (DAM) genes, in particular when microglia are exposed to amyloid plaques in vivo. Thus, γ-secretase regulates tonic signaling via a spectrum of substrates in microglia in steady state, and its blockage results in the defective transition to the DAM response in AD.
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Project description:Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies.
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Project description: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.
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Project description:Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, the roles of immune cell subsets in AD onset and progression are poorly understood. By transcriptional single cell sorting, we comprehensively map all immune populations in wild type and AD–transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify the markers, spatial-location, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices showed DAM with intracellular/phagocytic Aβ particles. Single cell analysis of DAM in Tg-AD and Trem2-/- Tg-AD revealed that the DAM program is activated in a two-step process. Activation is initiated in a Trem2 independent manner which involves down-regulation of microglia checkpoints, followed by activation of a Trem2-dependent program. These data identify a unique microglia-type, which may have important implications for future treatment of AD and other neurodegenerative diseases.
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Project description:The Apolipoprotein E4 (ApoE4) allele is one of the strongest risk factors for late-onset Alzheimer’s disease (AD) and is associated with a breakdown of the blood-brain barrier and vascular dysfunction (Nation et al 2019; Liu and Bu 2022). Importantly, these vascular pathologies are exacerbated when APOE4 is coexpressed with familial mutations in APP or components of the γ-secretase complex (Montagne and Zlokovic 2021), suggesting that the interactions between APOE4 and AD mutations can drive progression of the disease. However, most studies have been done in aging animals and few look at the impact of APOE4 expression in young animals and how that potentially contributes toward late-stage disease susceptibility. Here, we examined the potential functional interaction between APP mutations and ApoE4 in the progression of AD pathophysiology by comparing the hippocampal transcriptomes of 3-month-old female mice of 4 different genotypes: AppNL-G-F/NL-G-F , which harbours three knock-in mutations in the humanised Aβ region of APP (APP-TKI; Saito et al., 2014), mice with a single allele of human ApoE4 knocked-in, ApoE4+/wt (ApoE4), crosses of these two mouse lines, to create AppNL-G-F/NL-G-F;Apoe4+/wt (double-mutant or DM) mice, and wild-type (WT) mice that served as controls. RNAseq revealed nascent microglial activation signatures in both APP-TKI and double mutant datasets, as well as subtle but significant differences between APP-TKI and double mutant in expression of a subset of vascular remodeling genes.
2024-04-30 | GSE242751 | GEO
Project description:Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene expression changes associated with AD pathology and TREM2 in 5XFAD mice and human AD by snRNA-seq. We confirmed the presence of Trem2-dependent DAM and identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
2019-12-31 | GSE140510 | GEO
Project description:Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene expression changes associated with AD pathology and TREM2 in 5XFAD mice and human AD by snRNA-seq. We confirmed the presence of Trem2-dependent DAM and identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
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Project description:Given that the γ-secretase substrate proteome identified in H9MG reveals its central role in microglial signaling-regulatory events, we reasoned that investigating the overall profile of the transcriptomes of the microglia would provide a good integrated read-out for the overall context-dependent effect of blocking the processing of >85 γ-secretase substrates. Although the alteration in tonic signaling caused by γ-secretase inhibition does not change the overall cell state, i.e. the cells with γ-secretase deficiency do not cluster dramatically differently in the UMAP plots (Figure 4E-F and J-K), the tonic signaling is robust as it remains discernible in the background of a strong LPS-induced response (Figure 4H and M).
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