Demyelinating processes in aging and stroke in the central nervous system and the prospect of treatment strategy

Abstract

Demyelination occurs in response to brain injury and is observed in many neurodegenerative diseases. Myelin is synthesized from oligodendrocytes in the central nervous system, and oligodendrocyte death-induced demyelination is one of the mechanisms involved in white matter damage after stroke and neurodegeneration. Oligodendrocyte precursor cells (OPCs) exist in the brain of normal adults, and their differentiation into mature oligodendrocytes play a central role in remyelination. Although the differentiation and maturity of OPCs drive endogenous efforts for remyelination, the failure of axons to remyelinate is still the biggest obstacle to brain repair after injury or diseases. In recent years, studies have made attempts to promote remyelination after brain injury and disease, but its cellular or molecular mechanism is not yet fully understood. In this review, we discuss recent studies examining the demyelination process and potential therapeutic strategies for remyelination in aging and stroke. Based on our current understanding of the cellular and molecular mechanisms underlying remyelination, we hypothesize that myelin and oligodendrocytes are viable therapeutic targets to mitigate brain injury and to treat demyelinating-related neurodegeneration diseases.

Keywords: aging; demyelination; remyelination; stroke; white matter injury.

FIGURE 1

Demyelination and remyelination processes in aging, AD, and stroke. In aging and AD, vascular factors, microglial/astrocytic inflammatory factors, and β‐amyloid (Aβ) harms myelin integrity and OLs. Metabolism dysfunction involving fatty acids and cholesterol aggravate myelin breakdown. Epigenetic changes and absence of exogenous pro‐differentiation signals irreversibly burdens OPC proliferation/differentiation. Cholesterol limits microglia's clearance of myelin debris, which inhibits remyelination. In ischemic stroke, TIMP‐3 in astrocytes, and TNF‐α and MMP‐3 in microglia are induced, which increases caspase‐3 dependent OLs death and worsens demyelination injury. Microglia and infiltrating macrophages are activated to clear damaged myelin debris and dead neurons. Astrocytes also participate in the removal of dead cells and myelin debris through the ABCA1 pathway. Many molecular mechanisms are involved in remyelination after stroke. Reactive astrocytes secrete inhibin A and inhibit the expression of Matrilin‐2 in OPCs, which is not conducive to OPC differentiation and remyelination. NgR1 signaling is not conducive to the transformation of OPC into OLs. The cholesterol synthesis‐related ABCA1/ApoE/HDL signaling pathway promotes the migration of OPCs and the maturation of OLs after stroke. Interleukin‐4/PPARγ signal axis promotes OPC differentiation and maturation