Temporal and regional white matter vulnerability associated with Alzheimer's disease pathology

Abstract

Dementia is a term used to describe the loss of cognitive function that is sufficiently severe to impact daily activities and affects over 55 million people worldwide. Alzheimer’s disease (AD) is the leading cause of dementia, accounting for ~70% of cases. AD is a devastating age-associated disease that involves brain atrophy, neuronal loss and the accumulation of amyloid beta (Aβ) and tau protein aggregates. In recent years, there has been progress in developing disease-modifying treatments for AD. However, these drugs only show a modest clinical benefit and have significant side effects. Safer and more effective treatments are urgently needed. The white matter becomes compromised up to 20 years before the onset of AD symptoms. Yet, until recently, the contribution of white matter damage to AD has been largely understudied. White matter integrity is crucial for healthy cognitive function and damage to the white matter is predictive of cognitive decline. However, the neuropathological changes to the white matter during AD are unclear. In order to understand AD-associated white matter damage, I examined axon health, myelin integrity and the myelin-producing oligodendrocytes in the AppNL-G-F mouse model of AD. This is a second-generation model of AD that involves Aβ plaque deposition without the non-physiological overexpression of amyloid precursor protein (APP) seen in earlier mouse models. I investigated the cellular and molecular changes in the white matter across different regions and stages of pathology. AppNL-G-F mice showed no changes to oligodendrocyte lineage cell densities at 3 months of age, at the onset of Aβ plaque deposition. However, by 6 months of age, when cognitive deficits have been reported, there was a significant decrease in mature oligodendrocytes in the lateral white matter, which persisted at 9 months of age. Interestingly, the medial white matter was unaffected. This suggests that the lateral white matter region is vulnerable during the accumulation of AD pathology. The reduction in mature oligodendrocytes was followed by a loss of small diameter axons in the lateral white matter of 9-month-old AppNL-G-F mice. This suggests that oligodendrocyte loss leaves axons vulnerable to degeneration. To identify the mechanism underpinning oligodendrocyte vulnerability, digital spatial transcriptomics was performed. The molecular profiles of oligodendrocytes were examined in both medial and lateral white matter regions in AppNL-G-F and WT mice. Differential gene expression analysis revealed oligodendrocytes in the white matter of AppNL-G-F mice were enriched for genes involved in autophagy, an essential protein degradation pathway. Medial oligodendrocytes were enriched in genes associated with chaperone-mediated autophagy (CMA) while lateral oligodendrocytes were enriched in genes associated with macroautophagy and apoptosis. These data indicate that lateral oligodendrocytes undergo changes in protein degradation mechanisms which may leave them vulnerable to apoptotic cell death. The resulting oligodendrocyte loss might drive axon degeneration and contribute to AD-associated cognitive decline. Overall, this work demonstrates marked regional and temporal vulnerability of the white matter in the context of AD pathology. These data reveal novel cellular responses to AD pathology and highlight oligodendrocytes as a potential therapeutic target to prevent disease progression