Emerging Role of Oligodendrocytes Malfunction in the Progression of Alzheimer's Disease.

Abstract

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by hallmark pathologies such as amyloid-beta (Aβ) plaque accumulation, tau hyperphosphorylation, and progressive neuronal dysfunction. While much attention has focused on neurons and microglia, recent studies underscore the significant yet understudied roles of oligodendrocytes (OL) and oligodendrocyte precursor cells (OPC) in AD pathology. OL, responsible for myelin production and maintenance, are impaired early in AD, contributing to demyelination, synaptic dysfunction, and cognitive decline. Emerging evidence reveals that Aβ and tau pathology disrupt OPC differentiation and induce senescence, exacerbating neuroinflammation and reducing remyelination potential. Demyelination precedes overt AD symptoms, positioning it as a potential early biomarker. Furthermore, animal models reveal that OPC density and function deteriorate with age, particularly in the presence of Aβ plaques, highlighting their vulnerability in the AD environment. Transcriptomic studies also link cholesterol biosynthesis and lipid metabolism dysregulation in OPC to AD progression, emphasizing the intricate relationship between OL, metabolic processes, and amyloid toxicity. Additionally, the identification of disease-associated oligodendrocytes (DAO), characterized by altered gene expression and proximity to Aβ plaques, highlights their involvement in neuroinflammation and APP processing. This review synthesizes recent insights into OL and OPC dysfunction in AD, focusing on their roles in neuroinflammation, Aβ clearance, and myelin integrity. It discusses the potential of targeting OL and OPC pathways, such as enhancing remyelination and mitigating senescence, as novel therapeutic strategies. By addressing gaps in our understanding of OL dynamics, this work sheds light on their critical contributions to AD pathology and sets the stage for future research and intervention.