TGF-β signaling mediates microglial resilience to age-dependent dorsal column myelin alterations
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PROVIDER: PRJNA1072623 | ENA |
REPOSITORIES: ENA
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Project description:Microglia survey and regulate central nervous system myelination during development and homeostasis. However, whether microglia-myelin interactions are anatomically regulated remains unexplored. Herein, by exploring the spinal cord, which contains several white matter tracts, we demonstrate age-dependent myelin ultrastructural abnormalities occurring in the dorsal column (DC) but not the ventral column (VC). Transcriptomic analyses comparing aged and young spinal cords reveal major changes in genes regulating myelin, microglial function, and the TGF-β signaling pathway. The TGF-β signaling pathway is upregulated in the spinal cord with aging, and a TGFβ-enriched microenvironment is induced in the DC. Disrupting TGFβ1-TGFBR1/2 axis in microglia, by altering either ligand or receptor expression, leads to increased microglial activation, abnormal phagocytic behavior, and myelin loss in the DC, accompanied by neurological deficits more severe in older mice. snRNA-seq reveals a TGF-β signaling-sensitive microglial subset in the spinal cord, spatially restricted in the DC. These findings demonstrate that TGF-β signaling is indispensable for maintaining microglial resilience to myelin alterations in the DC during the aging process, highlighting a previously unresolved checkpoint mechanism of TGF-β signaling with regional specificity.
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Project description:Pathogenic tau accumulation fuels neurodegeneration in Alzheimer’s disease (AD). The role of microglia in tau-driven neurodegeneration is intricate, with DAP12 (DNAX-activation protein 12) triggering microglial immune responses. Mice lacking DAP12 become resistant to tau-induced brain toxicity in tauopathy mice, yet the precise mechanism remains elusive. Our current study uncovers a novel resilience mechanism against tau toxicity conferred by Dap12 deletion. While inactivation of Dap12 elevates tau inclusions, potentially disrupting microglial tau processing, it curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli) are abolished by removal of Dap12. Additionally, AD brains exhibit mouse iOli-like cells spatially correlated with tau pathology. In summary, our study reveals that DAP12 signaling triggers toxic interactions between microglia and oligodendrocytes in tauopathy, mediating tau-induced damage to oligodendrocytes and synaptic loss. Targeting DAP12 signaling presents a promising therapeutic approach for enhancing resilience against tau toxicity in AD.
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