Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-?-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model
Author(s): Ming Tong, Howard Gonzalez-Navarrete, Tyler Kirchberg, Billy Gotama, Emine B Yalcin, Jared Kay and Suzanne M de la Monte
Background. Alcohol-induced white matter (WM) degeneration is linked to cognitive-motor deficits and impaired insulin/IGF and Notch networks that regulate oligodendrocyte function. Ethanol also down-regulates expression of ASPH which drives Notch. Objective. Experiments were designed to determine if alcohol-related WM atrophy was linked to inhibition of ASPH and Notch. Methods. Adult Long Evans rats were fed for 3, 6, or 8 weeks with liquid diets containing 0% or 26% ethanol (caloric). During the last 2 weeks of each endpoint, ethanol-exposed rats were binged with 2 g/kg ethanol, 3×/week. Frontal lobe and cerebellar histological sections were used for image analysis and frontal WMwas used for protein studies. Results. Ethanol caused exposure duration-dependent reductions in frontal and cerebellar WM content. WM atrophy was associated with reduced expression of ASPH, Jagged-1, HES-1, and HIF-1α. Conclusions. These new findings link ethanol-induced WM atrophy to inhibition of ASPH expression and Notch network signaling, providing additional potential targets for treatment of alcoholic brain disease.