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

The impact of alcohol abuse on 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 single nucleus RNA sequencing of 113,242 cells. Several genes previously associated with AD in humans by GWAS were differentially regulated in specific neuronal populations. Gene expression patterns of AD mice with a history of alcohol intoxication were more similar to the gene expression signatures of older AD mice with more advanced disease and cognitive impairment than to 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. Overall design: Single nucleus RNA-Seq of the prefrontal cortex of 16 male 3xTg-AD and WT mice with and without histories of repeated alcohol intoxication through exposure to alcohol vapor (n=4).