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Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke.
Brain 2024 January 31
Ischemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserve neurons and promote functional recovery remain unavailable. Oligodendrocytes (OLs), the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischemic stroke. Technically, new OLs and myelin can be generated from the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischemic stroke remain poorly understood. Here, we reported numerous denuded axons in the lesion of human brain sections with ischemic stroke, accompanied by decreased neuron density, suggesting neuron loss correlates with myelin deficits in the stroke lesion. To understand the longitudinal changes of myelin dynamics after stroke, we label and trace pre-existing or newly-formed myelin, respectively, by using cell-specific genetic approaches. Our results indicated massive OLs death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remains insufficient 4- and 8-weeks post-stroke. Notably, neuronal loss and functional impairments are further deteriorated in aged brains, along with vanishing new myelin generation. To understand the causal relationship between remyelination and neuron survival, we manipulate myelinogenesis by conditional deletion of Olig2 (a positive regulator) or the muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibits remyelination, dampening neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R cKO or treating the pro-myelination drug clemastine after tMCAO preserves white matter integrity and neuronal survival, and accelerates functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischemic stroke.
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