The role of microglia in demyelination: insights into the impact of oligodendrocyte-secreted Serpina3n
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PROVIDER: PRJNA1212079 | ENA |
REPOSITORIES: ENA
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Project description:Microglia, the primary immune cells of the central nervous system, play critical roles in demyelination process. This study investigates the transcriptional changes in microglia associated with demyelination and examines the role of oligodendrocyte-secreted Serpina3n in modulating microglial responses during this pathological process. Bulk RNA sequencing was conducted on microglia isolated from mice subjected to a 4-week cuprizone diet, a model of demyelination. The experimental groups included: (1) normal control mice (Norm_Ctrl), (2) cuprizone-treated wild-type mice (CPZ_Ctrl), and (3) cuprizone-treated Olig2-Cre Serpina3n flox/flox mice (CPZ_cKO). Microglia were purified from mouse brains using magnetic-activated cell sorting (MACS). The results of this study aim to deepen our understanding of olidodendroglial Serpina3n’s role in shaping microglial behavior during demyelination and could inform potential therapeutic strategies for demyelinating diseases.
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Project description:Microglia, the resident immune cells of the central nervous system (CNS), are important regulators of normal brain activities. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Based on the observation of diminished Dicer positive microglia/macrophages number in demyelinating white matter lesions (WMLs) of human MS brains, here we probed the impact of impaired microRNA (miRNA)-mediated post-transcriptional gene regulation in a mouse model lacking microglia/macrophage-specific Dicer1 expression during demyelination and remyelination. Conditional Dicer1 ablation and loss of miRNAs expression in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting oligodendrocyte progenitor cells (OPCs) in the precursor stage. At the transcriptional level, Dicer1-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, finding from this study highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination.
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Project description:Alzheimer’s disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. Here, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the role of sex chromosomes and gonads in modifying microglia and oligodendrocyte responses before and after myelin loss. In an AD-related mouse model expressing APOE4, XY sex chromosomes heightened interferon response and tau-induced demyelination. The X-linked gene Toll-like receptor 7 (Tlr7) regulated sex-specific interferon response to myelin. Deletion of Tlr7 dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that Tlr7 plays a role in the male-biased IFN-I response in aging- and AD-related demyelination.
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Project description:We examined the role of TREM2 on microglia responses to demyelination Microglia were FACS-purified from WT or Trem2-/- mice fed with 0.2% cuprizone diet.
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Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
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