Schwann Cells

Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved in various aspects of cognition, with adaptive myelination playing a critical role in memory consolidation and motor learning. However, these physiological processes can be disrupted in various diseases. Understanding the mechanisms underlying myelin pathology is therefore essential for the development of targeted therapies for associated medical conditions. This review provides a comprehensive overview of the role of myelin in neural function, with a particular focus on adaptive myelination in cognition. We also highlight myelin dysfunction and the underlying mechanisms in the aging brain, as well as in diverse brain disorders and neurological conditions, including neurodegenerative diseases, psychiatric conditions, brain injuries, chemotherapy-related cognitive impairment, and neurological symptoms associated with COVID-19. Furthermore, we discuss the therapeutic potential of recently identified pro-myelinating compounds in aging-associated cognitive decline and brain disorders, as well as the future of remyelination therapies. Current evidence suggests that restoring functional myelin may serve as a therapeutic strategy for various medical conditions associated with myelin dysfunction.

Rationale: Damage to white matter and myelin poses a significant challenge to neurological recovery in the chronic phase of intracerebral hemorrhage (ICH). The repair of myelin damage post-ICH largely depends on the activation and differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes, a process that is significantly influenced by the inflammatory microenvironment. Lipocalin-2 (Lcn2) regulate phenotypic transformation of microglia and thus modulates inflammation. However, the exact role of Lcn2 in facilitating myelin recovery during the chronic phase of ICH remains to be fully understood. Methods: To create the ICH model, autologous blood from male C57BL/6 and Lcn2fl/flCx3cr1Cre mice was utilized. Behavioral tests were conducted to evaluate neurological recovery. The differentiation of OPCs and extent of myelin recovery were assessed using OPC and myelin markers. A multi-factor inflammatory chip was employed to investigate potential molecular regulatory mechanisms. Additionally, the Lcn2 inhibitor ZINC-94/89 was administered to explore its potential in targeting Lcn2 for enhancing myelin recovery during the chronic phase of ICH. Results: Knocking out Lcn2 in microglia significantly improved behavioral performance in chronic ICH mice, reduced inflammatory response, and enhanced myelin recovery. Both in vivo and in vitro experiments confirmed that Lcn2 knockout promoted microglia transformation to the M2 phenotype and enhanced OPCs differentiation. Mechanistically, Lcn2 knockout might affect Gdf-1 secretion in BV2 cells by modulating the JAK/STAT signaling pathway. Treatment with JAK inhibitors decreased Gdf-1 expression in BV2 cells, inhibiting OPCs migration and differentiation. Additionally, phosphorylation of Stat3 at Thr705 plays a critical role in enhancing Gdf-1 transcription and translation. Administration of the Lcn2 inhibitor ZINC-94/89 significantly improved behavioral performance, reduced inflammatory response, and promoted myelin recovery in chronic ICH mice. Conclusions: Lcn2 is crucial for myelin recovery in the chronic phase of ICH by modulating microglial phenotypes, thereby enhancing the migration and differentiation of OPCs. Administering an Lcn2 inhibitor early on could serve as a novel and effective strategy to boost recovery during this phase.

Aging is the major risk factor for Alzheimer's disease (AD). In the aged brain, myelin debris accumulates and is cleared by microglia. Phagocytosed myelin debris increases neutral lipid droplet content in microglia. Neutral lipids include cholesteryl esters (CE) and triacylglycerol (TAG). To examine the effects of myelin debris on neutral lipid content in microglia, we added myelin debris to human HMC3 and mouse N9 cells. The results obtained when using 3H-oleate as a precursor in intact cells reveal that myelin debris significantly increases the biosynthesis of CE but not TAG. Mass analyses have shown that myelin debris increases both CE and TAG. The increase in CE biosynthesis was abolished using inhibitors of the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). ACAT1 inhibitors are promising drug candidates for AD treatment. In myelin debris-loaded microglia, treatment with two different ACAT1 inhibitors, K604 and F12511, increased the mRNA and protein content of ATP-binding cassette subfamily A1 (ABCA1), a protein that is located at the plasma membrane and which controls cellular cholesterol disposal. The effect of the ACAT1 inhibitor on ABCA1 was abolished by preincubating cells with the liver X receptor (LXR) antagonist GSK2033. We conclude that ACAT1 inhibitors prevent the accumulation of cholesterol and CE in myelin debris-treated microglia by activating ABCA1 gene expression via the LXR pathway.

Myelin damage is a hallmark of several neurological disorders, but how it occurs remains to be fully understood. In this study, we found that early damage in zebrafish and rodent demyelination models is characterized by myelin swelling. We show, through live imaging, that myelin swelling does not always lead to myelin loss and that swellings can sometimes resolve, allowing sheaths to remodel. Increased neuronal activity during early demyelination exacerbates myelin damage, whereas reducing neuronal activity mitigates myelin swelling in both zebrafish and mice. In human multiple sclerosis tissue, myelin swelling is also dynamic and is prominent around active lesions. Our data indicate that myelin swelling is a conserved feature of demyelination and that damage to myelin sheaths can resolve, opening opportunities for targeting human disease.