Demyelination in Vascular Dementia: Focus on Oligodendrocytes, Microglia, and Their Interaction.

Abstract

Vascular dementia (VaD), a primary cognitive disorder caused by cerebrovascular pathology, features significant white matter damage from chronic cerebral hypoperfusion strongly correlated with cognitive decline. Myelin integrity disruption represents a core pathological foundation in VaD, with dysfunctional oligodendrocytes (OLs) and microglia (MG) forming a critical pathogenic nexus. OLs govern myelin formation and maintenance while MGs modulate myelination through cerebral microenvironment regulation. In the central nervous system, precise communication and synergistic interaction between cells are the basis for maintaining homeostasis and cognitive function. The complement system, cytokine network, and extracellular vesicles together form its core communication axis. The complement system is at the forefront of the rapid innate immune response, cytokines dynamically regulate the initiation and resolution of inflammation, as carriers of functional molecules between cells, extracellular vesicles target and deliver information of bioactive molecules, upgrading intercellular communication to an active and programmed network regulation system. The three work together to maintain the homeostasis of the neural microenvironment. Their dysregulation can lead to uncontrolled neuroinflammation and tissue damage, which is the core pathological link in diseases such as VaD. This review examines the interplay between OLs and MG in VaD demyelination, detailing their complex communication networks via the complement system (including C1q, C3, C5 fragments), key cytokines (TNF-α, IL-1β, IL-4, IL-10), and extracellular vesicle signaling. Notably, these pathways exhibit bidirectionality: moderate activation promotes repair mechanisms, whereas excessive responses exacerbate injury. Future research should elucidate the spatiotemporal dynamics of OLs-MG interactions and identify precise therapeutic targets to restore cellular equilibrium, thereby informing novel VaD intervention strategies.