Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California 92037
Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
eNeuro. 2023 Jul 7;10(7). doi: 10.1523/ENEURO.0456-22.2023. Print 2023 Jul.
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. The gene expression signatures of AD mice with a history of alcohol intoxication showed greater similarity to the signatures of older AD mice with advanced disease and cognitive impairment than did the gene expression signatures of AD mice not exposed to alcohol, 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.
酗酒对阿尔茨海默病（AD）的影响知之甚少。在这里，我们通过酒精蒸气暴露发现，AD 小鼠模型中神经认知障碍的发作因反复酗酒而加速，并通过对 113242 个细胞进行单细胞 RNA 测序提供了前额叶皮层的综合基因表达数据集。我们观察到广泛的基因表达失调，涉及神经元兴奋性、神经退行性变和炎症，包括干扰素基因。几项先前通过全基因组关联研究与人类 AD 相关的基因在特定神经元群体中存在差异调节。有酗酒史的 AD 小鼠的基因表达特征与疾病进展和认知障碍更严重的老年 AD 小鼠的基因表达特征更相似，而未接触酒精的 AD 小鼠的基因表达特征则不相似，这表明酒精促进了与 AD 进展一致的转录变化。我们在单细胞水平的基因表达数据集为研究过量饮酒对 AD 的有害作用的分子基础提供了独特的资源。
