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

Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-beta (A beta)-related pathology, metabolism, and behavior. 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 drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Com-plementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates A beta in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF A beta 40, but not ISF A beta 42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-D-aspartate receptor (NMDAR) and decreased gamma-aminobutyric acid type-A receptor (GABAAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase A beta deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction be-tween alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.

Automated summary

This study used a moderate drinking paradigm to investigate the effects of chronic ethanol exposure on Alzheimer's disease-related pathology, behavior, and metabolism. Ethanol-exposed mice showed increased brain atrophy, amyloid plaques, and shifts in plaque size distribution. They also exhibited deficits in self-care, increased locomotor activity, altered feeding behavior, and changes in glucose homeostasis. These findings suggest that ethanol may increase A beta deposition by disrupting metabolism and the brain's E/I balance, ultimately leading to AD-related phenotypes.