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Presentation date

Summer 8-12-2021

College, Institute, or Department

Pharmacology and Experimental Neuroscience

Faculty Mentor

Dr. Shilpa Buch

Research Mentor

Dr. Susmita Sil

Abstract

Alcohol use is widespread, with 85.6 percent of people ages 18 and older reported drinking alcohol in their lifetime in 2019. Mild to heavy alcohol use is associated with multi-organ dysfunction at the cellular and genetic levels, as well as epigenetic modifications, leading to liver and brain damage and dementia. The role of astrocytes as contributors to Alzheimer’s like pathology associated with cognitive decline in opiate abusers and people with HIV-associated neurological disorders (HAND) has been recently reported from our group. We hypothesize that alcohol could also induce astrocytic amyloidosis. In this study we demonstrated that exposure of human primary astrocytes (HPA) to ethanol resulted in a dose dependent (6.25-200 mM) increase in AD markers-amyloid precursor protein (APP), Aβ 1-42, β-site cleaving enzyme (BACE1), as well as the inflammatory marker IL1βand lncRNA BACE1AS. Next, we demonstrated a time-dependent (0-96h, 12.5 mM) upregulation of AD markers, oxidative stress (4-HNE), alcohol metabolizing enzymes alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH2), and cytochrome P450 2E1 (CYP2E1), as well as proinflammatory cytokines (TNF-α, IL1β, IL6) in HPAs exposed to alcohol. Gene silencing approaches confirmed the regulatory role of lncRNA BACE1-AS in amyloidosis and its interaction with alcohol metabolic pathways leading to neuroinflammation and oxidative stress. Further, in vivo study validated our in vitro findings, demonstrating up-regulation of APP, Aβ1-42, 4-HNE and IL1β in the cortices of ethanol-fed mice (4- weeks, ad libidum) compared to saline controls. This is the first report implicating the role of lncRNA BACE-AS in alcohol-mediated induction of astrocytic amyloidosis, leading to neuroinflammation and oxidative stress, which, in turn, could contribute to cognitive impairments. These findings set the stage for future development of therapeutic strategies aimed at targeting cognitive deficits in alcohol users and abusers.

Keywords

Alcohol, Alzheimer's Disease, BACE1-antisense, Cognitive Impairment

Alcohol in dementia: Implications of Alzheimer’s like pathology in alcohol abuse

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