A history of repeated alcohol intoxication promotes cognitive impairment and gene expression signatures of disease progression in the 3xTg mouse model of Alzheimer's disease.

Abstract

The impact of alcohol abuse on Alzheimer's disease (AD) is poorly understood. Here, we show that the onset of neurocognitive impairment in a mouse model of AD is hastened by repeated alcohol intoxication through exposure to alcohol vapor, and we provide a comprehensive gene expression dataset of the prefrontal cortex by the single-nucleus RNA sequencing of 113,242 cells. We observed a broad dysregulation of gene expression that involves neuronal excitability, neurodegeneration, and inflammation, including interferon genes. Several genes previously associated with AD in humans by genome-wide association studies were differentially regulated in specific neuronal populations. Gene expression patterns of AD mice with a history of alcohol intoxication were more similar to gene expression signatures of older AD mice with more advanced disease and cognitive impairment than those of younger AD mice with prodromic disease, suggesting that alcohol promotes transcriptional changes consistent with AD progression. Our gene expression dataset at the single-cell level provides a unique resource for investigations of the molecular bases of the detrimental role of excessive alcohol intake in AD.Significance statementAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Many efforts have been geared toward the identification of environmental and genetic risk factors. However, alcohol has received limited attention as a potential risk factor for AD. We explored effects of the interaction of a history of alcohol intoxication with genetic AD susceptibility on cognitive performance and gene expression at the single-cell level. We found that a history of repeated alcohol intoxication promotes the emergence of spatial learning and memory impairments in pre-symptomatic triple transgenic AD (3xTg-AD) mice. We also show that a history of repeated alcohol intoxication induces prefrontal cortex transcriptional changes associated with AD progression.