Age-impaired remyelination is associated with dysregulated microglial transitions.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE281947 | GEO | 2025/08/01
REPOSITORIES: GEO
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Project description:The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.
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Project description:The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.
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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:We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor found on microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases and analyzed the impact of the antibody on myelination and gene expression in single cells. We found that blocking TREM2 depleted a specific population of microglia characterized by high expression of the transcription factor MAFB during remyelination. These MAFB-high microglia were crucial for myelin repair, and their depletion led to impairment of myelinating oligodendrocytes. Importantly, we identified MAFB+ microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that are critical for myelin repair. This finding has important implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a potential therapeutic strategy.
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Project description:The efficiency of central nervous system (CNS) remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study we show that expression of genes involved in the retinoid X receptor (RXR) pathway are decreased with aging in myelin-phagocytosing cells. Loss of RXR function in young macrophages mimics aging by delaying remyelination after experimentally-induced demyelination, while RXR agonists partially restore myelin debris phagocytosis in aged macrophages. The FDA-approved RXR agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in aging human monocytes to a more youthful profile. These results reveal the RXR pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics. 24 Human CD14+ monocyte-sorted PBMC samples representing 4 Healthy Volunteers (HV) and 4 Multiple Sclerosis (MS) patients under 3 different treatment conditions. Condition 1 = (-) Phagocystosis (-) Bexarotene. Condition 2 = (+) Phagocystosis (-) Bexarotene. Condition 3 = (+) Phagocystosis (+) Bexarotene.
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Project description:Microglia are considered both pathogenic and protective during recovery from demyelination, but their precise role remains ill-defined. Here, using an inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, and mice infected with a neurotropic coronavirus (mouse hepatitis virus, strain JHMV), we show that depletion of microglia after clearance of virus infection resulted in impaired myelin repair and prolonged clinical disease. Microglia were required only during the early stages of remyelination. Notably, large deposits of extracellular vesiculated myelin and cellular debris were detected in the spinal cords of PLX5622-treated and not control mice, which correlated with decreased numbers of oligodendrocytes in demyelinating lesions in drug-treated mice. Further, gene expression analyses demonstrated differential expression of genes involved in myelin debris clearance, lipid and cholesterol recycling, and promotion of oligodendrocyte function. The results also demonstrate that microglial function could not be compensated by infiltrating macrophages. Together, these results demonstrate key roles for microglia in debris clearance and the initiation of remyelination following infection with a neurotropic coronavirus but are not necessary during later stages of remyelination.
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Project description:Multiple Sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation in the central nervous system (CNS) that triggers demyelination, glial cell dysfunction and irreversible neuro-axonal damage1. While considerable progress has been made in treating early inflammatory relapsing-remitting MS, the mechanisms underpinning the progressive stage remain largely unknown. The capacity of microglia, the CNS-resident phagocytes, to clear tissue debris is essential for both maintaining and restoring CNS homeostasis2,3 and this capacity diminishes with age4-6. Age strongly associates with the risk of developing progressive MS7,8. Herein we demonstrate that the recovery from inflammation is dependent on the ability of microglia to clear tissue debris and that blocking this process leads to development of progressive disease in a murine model of MS. Microglia-specific deletion of the general autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin. This further associated with the alteration of the microglial phenotype towards that previously described in other neurodegenerative diseases2,3,9. Moreover, Atg7 deficient microglia showed striking similarities with microglia from aged wild type mice, which also demonstrated accumulation of myelin debris and inability to recover from MS-like disease. In contrast, the induction of autophagy using the disaccharide Trehalose in aged mice led to functional myelin clearance and remission from MS-like disease. Our results demonstrate that a non-canonical form of autophagy in microglia is responsible for myelin clearance and that impairment of this pathway markedly changes microglial phenotype and prevents recovery from MS-like disease. Importantly, we show that using a disaccharide ubiquitously found in plant-derived foods to boost autophagy in cells in which this process is naturally diminished can be utilized for therapeutic purposes.Project was run on 4 lanes with a 10M sequencing depth
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