Myelin Impairment and Regeneration in the Central Nervous System: Molecular Mechanisms, Diseases, and Prospective Therapeutic Targets

Abstract

Myelin plasticity is fundamental to the formation of neural networks and the optimization of neural functions, shaping circuits governing emotion, cognition, sensation, and motor control. Synthesized by oligodendrocytes, myelin undergoes lifelong remodeling that demands high metabolic activity; this renders the myelin-oligodendrocyte unit highly susceptible to metabolic stress, aging, and pathological insults. While demyelination is the core hallmark of various chronic neurological disorders, this review specifically highlights its emerging role in Alzheimer's disease (AD). Myelin impairment is increasingly recognized as an early pathological event in AD, potentially preceding the classic accumulation of amyloid plaques and neurofibrillary tangles. Here, we provide a comprehensive overview of myelin structure and function, evaluating the potential of tracking myelin changes as early diagnostic biomarker for AD. We further synthesize recent evidence regarding myelin pathology across a spectrum of central nervous system disorders including multiple sclerosis, leukodystrophies, cerebral small vessel disease, psychiatric disorders, and traumatic injury, highlighting the underlying pathological mechanisms. Furthermore, we examine emerging therapeutic strategies, ranging from pharmacological interventions to noninvasive stimulation, aimed at restoring oligodendroglial function and promoting remyelination. Finally, we offer a forward-looking perspective on myelin regeneration research, emphasizing its critical potential as a novel therapeutic target for AD and other neurodegenerative conditions.