Microglia and oligodendroglia in Alzheimer's disease

Abstract

Alzheimer’s disease is the most common form of dementia, characterized by the accumulation of β-amyloid plaques, neurofibrillary tangles composed of hyperphosphorylated tau protein, loss of synaptic connections and neurons, and pronounced neuroinflammation. Traditionally, the pathogenesis of Alzheimer’s disease was associated with neuronal death; however, accumulating evidence over the past decade convincingly demonstrates the critical role of glial cells — primarily microglia and oligodendrocytes — in the development, progression, and clinical manifestations of the disease. Microglia, as innate immune cells of the central nervous system, and oligodendrocytes, responsible for axonal myelination and trophic support, not only respond to pathological changes in Alzheimer’s disease but actively shape the microenvironment that either supports neuronal integrity or promotes neurodegeneration. In this context, studying the functional state, molecular activation mechanisms, and intercellular interactions of these glial cells is essential for understanding the pathogenesis of Alzheimer’s disease and developing new therapeutic strategies. The consequences of microglial and oligodendrocyte malfunction are closely interconnected functionally and pathophysiologically. Chronically reactive microglia can negatively affect the differentiation of oligodendrocyte precursor cells, while an excess of cytokines (TNF-α, IL-1β) inhibits remyelination. Conversely, damaged oligodendrocytes synthesize proteins that further activate microglia, creating a vicious cycle of glial malfunction. This interaction generates a pathological microenvironment characterized by sustained inflammation, oxidative stress, metabolic instability, and loss of neuronal function. Given this dynamic, it becomes clear that therapeutic strategies should not be limited to the removal of amyloid plaques or tau protein, but should also aim to restore the functional activity of glial cells, particularly microglia and oligodendrocytes. Thus, microglia and oligodendrocytes are active participants in the pathogenesis of Alzheimer’s disease. Their malfunction — especially chronic microglial activation and the loss of oligodendrocyte myelinating capacity — contributes to the progression of neurodegeneration. Understanding the molecular mechanisms of glial malfunction opens new opportunities for the development of targeted therapies, including modulation of microglial activation, support of energy metabolism, and promotion of remyelination — promising directions in the fight against Alzheimer’s disease.