Ethanol exposure alters Alzheimer’s-related pathology, behavior, and metabolism in APP/PS1 mice

Abstract

AbstractChronic ethanol exposure can increase amyloid-β (Aβ) and tau in rodent models of Alzheimer’s-disease (AD)-like pathology, yet the underlying mechanisms are poorly understood. In this study, a moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters Aβ-related pathology, metabolism, and behavior. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol also induced changes in N-methyl-D-aspartate and γ-aminobutyric acid type-A receptor (NMDAR and GABAAR, respectively) expression, possibly reflecting changes in the excitatory and inhibitory (E/I) balance in the brain. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Ethanol exposure also exacerbated alterations in the open-field test and deficits in nest-building behaviors in APP/PS1mice. Lastly, an acute dose of ethanol bidirectionally altered hippocampal ISF Aβ levels – decreasing during the initial exposure and increasing during withdrawal. Acute ethanol exposure increased hippocampal ISF glucose levels, suggesting changes in cerebral glucose metabolism occur in response to ethanol. These experiments indicate that ethanol exacerbates an AD-like phenotype by altering Aβ deposition, behavior, and metabolism. Here, even a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.HighlightsChronic ethanol exposure increases brain atrophy in APP/PS1 mice.Chronic ethanol exposure increased the number of plaques in the brains of APP/PS1 mice.Chronic ethanol exposure led to dysregulated metabolism in APP/PS1 mice.Chronic ethanol exposure altered anxiety- and dementia-related behaviors in APP/PS1 mice.Acute ethanol exposure bidirectionally alters interstitial fluid (ISF) levels of amyloid-β in APP/PS1 mice during exposure and withdrawal.