Molecular and biochemical pathologies in human alcohol-related cerebellar white matter degeneration

Alcohol use disorder (AUD) marked by heavy chronic or binge alcohol consumption, causes cerebellar and white matter (WM) atrophy with cognitive-motor impairments. Major pathological features of alcohol-related brain damage (ARBD) include alterations in WM integrity with myelin loss, and cerebellar degeneration with neuronal loss.

This study characterizes molecular and biochemical oligodendrocyte-related pathology in cerebellar tissue from donors with AUD to better understand the mechanisms of ARBD in humans.

Cores of cerebellar vermis, including cortex and underlying WM from adult human postmortem AUD and control brains, were processed for RNA and protein analyses using duplex and multiplex panels.

AUD cerebellar WM had significant alterations in immature and mature oligodendrocyte protein and mRNA expression, and reduced expression of hepatocyte growth factor, Akt and GSK-3β signaling molecules, and Notch pathway activation. Moreover, the only significant AUD-related alteration in cerebellar cytokine/chemokine expression was reduced IL-16 immunoreactivity.

Human AUD WM degeneration is associated with oligodendrocyte dysfunction, which mechanistically could be mediated by impairments in insulin/IGF signaling through Akt/GSK-3β or Notch pathway activation. Future studies should focus on the non-invasive detection and monitoring of AUD-related oligodendrocyte pathology through the analysis of cell-type-specific exosomes isolated from peripheral blood.