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 non-dependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology.We first evaluated the impact of voluntary 24-h, 2-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 ADassociated 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 wildtype 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 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.

Multi-omics integration analysis identifies novel genes for alcoholism with potential link to neurodegenerative diseases

“…Located on chromosome 17, MAPT, encodes the tau proteins best known medically for their role in central nervous system disorders such as Alzheimer's disease 38 , frontotemporal dementia 39 , Parkinson's disease 38 , and the primary tauopathies progressive supranuclear palsy and corticobasal degeneration 40 . Recently, Hoffman and colleagues 41 showed that alcohol use can upregulate the expression of pTau (Ser199/Ser202) in the hippocampus of C57BL/6J mice. Another study in humans observed differences in CSF-Tau levels in demented alcoholics vs Alzheimer disease patients 42 .…”

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 AD-like pathologies also associated with reduced phosphorylation of phosphoproteins associated with Akt/mTOR signaling pathway in a brain region-specific manner [amygdala: ERK 1/2 (Thr 185/Tyr 187); Lateral hippocampus: IRS1 (Ser 636), p7056K (Thr 389/412); CA1: mTOR (Ser 2448), PTEN (Ser 380); lateral entorhinal cortex: IGF1R (Tyr 1135/1736), IR (Tyr 1162/1163), PTEN (Ser 380); Medial entorhinal cortex: GSK 3α (Ser 21), IGF1R (Tyr 1135/1136), IRS1 (Ser 636), RP 56 (Ser 235/236)] ( 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 ).…”

“…Numerous other studies also have explored the function of mTOR kinases, including in mTORC1 and mTORC2 in alcohol-dependent AUD models ( Beckley et al, 2016 ; Laguesse et al, 2017 , 2018 ; Morisot et al, 2018 ; For review, Hanim et al, 2020 ). Future studies should extend the work of Hoffman et al (2019) in alcohol-dependent models as factors such as blood alcohol level, animal strain, and even brain regions could greatly influence the changes in Akt/mTOR signaling pathway.…”

Adolescent binge‐ethanol accelerates cognitive impairment and β‐amyloid production and dysregulates endocannabinoid signaling in the hippocampus of APP/PSE mice

“…One conceivable explanation for these opposite results is that, given that it is well known that the processes that regulate mRNA expression and 49 In animal models, there are only two recent papers where chronic EtOH has been demonstrated to aggravate learning and memory impairment and to exacerbate Aβ deposition several days after its administration in adult AZ mice. 32,50 Therefore, this is the first study evaluating the long-term effects of adolescent EtOH binge drinking in a rodent model of AD. We demonstrate that the administration of this treatment accelerates and F I G U R E 6 Effects of adolescent binge-EtOH exposure on hippocampal protein levels of CB2, DAGLα, and MAGL in wild-type (WT) and AZ mice at 6 months of age.…”

“…11,31 A recent study suggests that EtOH binge drinking aggravates Alzheimer-associated symptoms in a rodent model of AD. 32 However, the effects of EtOH consumption during adolescence in the course of AD has not been investigated.…”