Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model.

Ming Tong,Ming Tong,Emine B Yalcin,Suzanne M De La Monte,Suzanne M De La Monte,Tyler Kirchberg,Howard Gonzalez-Navarrete,Billy Gotama,Emine B Yalcin,Jared Kay,Billy Gotama

doi:10.4303/jdar/236033

Abstract

Alcohol-induced white matter (WM) degeneration is linked to cognitive-motor deficits and impairs insulin/insulin-like growth factor (IGF) and Notch networks regulating oligodendrocyte function. Ethanol downregulates Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) which drives Notch. These experiments determined if alcohol-related WM degeneration was linked to inhibition of ASPH and Notch. Adult Long Evans rats were fed for 3, 6 or 8 weeks with liquid diets containing 26% ethanol (caloric) and in the last two weeks prior to each endpoint they were binged with 2 g/kg ethanol, 3×/week. Controls were studied in parallel. Histological sections of the frontal lobe and cerebellar vermis were used for image analysis. Frontal WM proteins were used for Western blotting and duplex ELISAs. The ethanol exposures caused progressive reductions in frontal and cerebellar WM. Ethanol-mediated frontal WM atrophy was associated with reduced expression of ASPH, Jagged 1, HES-1, and HIF-1α. These findings link ethanol-induced WM atrophy to inhibition of ASPH expression and signaling through Notch networks, including HIF-1α.

Highlights

Consequences of alcohol abuse and addiction are among the costliest healthcare problems in the world
This study explores the potential role of impaired ASPH and Notch signaling as mediators of progressive ARBDassociated white matter (WM) atrophy
Standardized histological sections of frontal lobe and cerebellar vermis were used for image analysis to assess progressive changes in WM abundance following chronic+binge ethanol exposures

Summary

Introduction

Consequences of alcohol abuse and addiction are among the costliest healthcare problems in the world. Alcohol-related brain disease (ARBD) characterized by neurobehavioral abnormalities and cognitive deficits including impairments in executive function [4] can disrupt family and social relationships and progress to dementia and disability [5,6]. Ultrastructural studies of an experimental model demonstrated that WM atrophy following chronic heavy alcohol exposure is mediated by combined effects of demyelination, dysmyelination, and axonal degeneration [20]. The finding that chronic ethanol exposures broadly alter oligodendrocyte myelin-associated gene expression [21,22] suggests that the neurotoxic and degenerative effects of alcohol include oligodendrocyte dysfunction

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