Dysregulated oligodendrocyte and myelin dynamics as an early pathological feature of neuropil degeneration in Alzheimer's disease: an ultrastructural study

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by the accumulation of amyloid-beta plaques and neurofibrillary tangles. Increasing evidence suggests that white-matter degeneration and myelin disruption occur early in disease progression and may contribute to neuropathological vulnerability. Here, we performed ultrastructural analyses in the 3xTg and 5xFAD mouse models of AD across developmental stages (3-12 months of age), including ages preceding overt amyloid plaque formation or neuronal loss. We identify a spectrum of oligodendrocyte- and myelin-associated abnormalities, including single-membrane herniations, myelin outfolds, and ectopic myelination of neuronal processes, which are evident as early as 3 months of age and are frequently associated with altered neuropil architecture and incipient dystrophic neurite morphology. These malformations were confirmed to be oligodendrocyte-derived through O4 immunolabeling. Collectively, our findings reveal early, widespread myelin-associated ultrastructural alterations that form a consistent structural component of neuritic pathology in AD models. We propose that dysregulated oligodendrocyte membrane remodeling represents an early pathological feature of AD, providing a framework for future studies examining how glial pathology intersects with neuronal degeneration and plaque-associated neuritic remodeling.