Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer’s pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

Alcohol Use Disorder, Neurodegeneration, Alzheimer’s and Parkinson’s Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

“…Laboratory findings revealed an increase in Aβ 42/40 ratio in lateral entorhinal and prefrontal cortex, total Tau expression in medial prefrontal cortex, lateral entorhinal cortex, amygdala, and phosphorylated tau expression (Ser 199/Ser 202) in hippocampus. The ADlike pathologies also associated with reduced phosphorylation of phosphoproteins associated with Akt/mTOR signaling pathway in a brain region-specific manner (Hoffman et al, 2019). In agreement with these findings, the Akt/mTOR pathway was reported to respond selectively in a brain region-specific manner in a binge-intake alcohol dependent AUD model (Laguesse et al, 2017).…”

Role of Alcohol Drinking in Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis

“…GSK3β phosphorylation is increased after acute and chronic alcohol exposure. One recent study showed hyperphosphorylation at the GSK3 site on Tau protein in the hippocampus (CA1) subregion of a 3xTg-AD mouse brain 1 month post alcohol drinking, suggesting that chronic alcohol drinking has detrimental effects in AD [35].…”

“…Higher concentrations of ethanol contribute to increased accumulation/production of Aβ and the precursor protein [34]. One recent study showed that alcohol drinking in the tripletransgenic model of AD (3xTg-AD) mice induced deficits in cognitive and emotional functions compared to wild-type controls, and induced pathological changes such as the hyperphosphorylation of Tau-Ser199/202 in neuronal cell bodies and the dorsal hippocampus (CA1) in 3xTg-AD mice 1 month post alcohol drinking [35]. Alcohol has been suggested to be either protective of, or not associated with PD [36].…”

“…In this article, we review the main neurological effects of alcohol intake on neurological disorders and describe the epidemiological and experimental relationships between alcohol consumption and major neurodegenerative diseases such as AD, PD and ALS. [35]. In PD, most studies show that alcohol decreases levels of DA and increases the levels of αSYN.…”

“…There is a dysfunction of the glutamatergic excitatory system in ALS, and chronic alcohol intake involves changes in glutamatergic transmission. [35]. In PD, most studies show that alcohol decreases levels of DA and increases the levels of αSYN.…”