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

Abstract

Previous research in rodents suggests that the long-term neurobehavioral disturbances induced by chronic ethanol (EtOH) exposure could be due to endocannabinoid system (ECS) alterations. Moreover, ECS failure has been proposed to mediate the cognitive impairment and β-amyloid production in Alzheimer disease (AD). Thus, in the present study, we evaluated the effects of adolescent EtOH binge drinking on the cognitive disturbances, hippocampal β-amyloid levels, and in the ECS expression on a transgenic mouse model (APP/PSEN, AZ) of AD. We exposed AZ and wild-type mice to a binge-drinking treatment during adolescence. At 6 and 12 months of age, we evaluated hippocampal-dependent learning and memory: β-amyloid concentrations and RNA and protein levels of cannabinoid type-2 receptors (CB2), diacylglycerol lipase-α (DAGLα), and monoacylglycerol lipase (MAGL) in the hippocampus. The results showed that binge-EtOH treatment worsens cognitive function and increases β-amyloid levels in AZ. At 6 months, EtOH heightens CB2 (RNA and protein) and DAGLα (RNA) expression in wild type but not in AZ. On the contrary, EtOH enhances MAGL RNA expression only in AZ. At 12 months, AZ displays increased levels of CB2 (RNA and protein) and DAGLα (protein) compared with control. Similar to what happens at 6 months, EtOH induces an increase in CB2 gene expression in wild type but not in AZ; however, it augments CB2 and DAGLα protein levels in both genotypes. Therefore, we propose that adolescent binge drinking accelerates cognitive deficits associated with aging and AD. It also accelerates hippocampal β-amyloid accumulation in AZ and affects differently the ECS response in wild type and AZ.

Adolescent Binge Alcohol Enhances Early Alzheimer’s Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation

“…A prior study using a daily binge model with i.p. injection of ethanol (2.5 g/kg) across adolescence (P20-P60) in APP/PSE mice found similar increases in protein levels of Aβ42 in the hippocampus at 6 and 12 months of age, with no effects in wild type mice ( Ledesma et al, 2021 ). A study by Hoffman et al (2019) with voluntary drinking with lower BACs in adult 3xTg-AD mice showed increased staining of p-tau-199/202 in CA1 of the hippocampus and increased Aβ42/40 protein ratios in cortical brain regions 1 month after ethanol with no effects in wild type mice.…”

“…Further, heavy alcohol use was the number one modifiable risk factor for AD and all-cause dementia in a French study that assessed over a million patients ( Schwarzinger et al, 2018 ). A recent preclinical study similarly found that adolescent binge ethanol increased AD pathology in an amyloid-expressing transgenic mouse model ( Ledesma et al, 2021 ). Thus, binge alcohol use during adolescence is emerging as a key risk factor for AD.…”

Chronic Ethanol Causes Persistent Increases in Alzheimer’s Tau Pathology in Female 3xTg-AD Mice: A Potential Role for Lysosomal Impairment

“…A recent study in APP/PSE mice using a daily binge model ethanol (2.5g/kg, i.p.) during adolescence (P20–P60) found persistent increases in protein levels of Aβ42 in the hippocampus at 6 and 12 months of age and causes working memory deficits ( Ledesma et al, 2021 ). Another study by Hoffman et al (2019) using voluntary drinking (moderate exposure) in 10-week-old adult 3xTg-AD mice for 4 months showed increased levels of p-tau-199/202 in hippocampus and increased Aβ42/40 ratios in cortex that persisted one month into ethanol abstinence (7 months of age at assessment) with reduced memory retention in the probe trial of the Morris water maze.…”

“…The majority of wild-type mouse strains do not develop AD-like pathology. Accordingly, the aforementioned studies assessing the effect of ethanol on AD pathology did study wild type mice, finding no effects of ethanol on amyloid or tau in wild type mice ( Hoffman et al, 2019 ; Ledesma et al, 2021 ). However, studies in adolescent wild type mice find ethanol does persistently promote proinflammatory signaling ( Vetreno and Crews, 2012 ; Montesinos et al, 2015 ) though it is unclear if this occurs in adults.…”

Alcohol-Drinking Under Limited-Access Procedures During Mature Adulthood Accelerates the Onset of Cognitive Impairment in Mice

“…Even light-to-moderate alcohol consumption (<8 drinks/week) is associated with cognitive decline (e.g., Topiwala et al, 2017 ), while heavy alcohol drinking (<14 drinks/week) is reported to significantly increase the likelihood of developing dementia (Weyerer et al, 2011 ; Xu et al, 2017 ; Huang et al, 2018 ; Sabia et al, 2018 ). Excessive alcohol consumption is reported to reduce the age of dementia-onset in humans (Ledesma et al, 2020 ), as well as in laboratory rodents (e.g., Crews and Vetreno, 2014 ; Hoffman et al, 2019 ). Epidemiological data identify AUDs as the strongest modifiable risk factor for dementia onset, accounting for approximately 60% of early-onset dementia cases (Schwarzinger et al, 2018 ).…”