Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
Cells. 2024 Jul 10;13(14):1173. doi: 10.3390/cells13141173.
As per the National Survey on Drug Use and Health, 10.5% of Americans aged 12 years and older are suffering from alcohol use disorder, with a wide range of neurological disorders. Alcohol-mediated neurological disorders can be linked to Alzheimer's-like pathology, which has not been well studied. We hypothesize that alcohol exposure can induce astrocytic amyloidosis, which can be corroborated by the neurological disorders observed in alcohol use disorder. In this study, we demonstrated that the exposure of astrocytes to ethanol resulted in an increase in Alzheimer's disease markers-the amyloid precursor protein, Aβ1-42, and the β-site-cleaving enzyme; an oxidative stress marker-4HNE; proinflammatory cytokines-TNF-α, IL1β, and IL6; lncRNA BACE1-AS; and alcohol-metabolizing enzymes-alcohol dehydrogenase, aldehyde dehydrogenase-2, and cytochrome P450 2E1. A gene-silencing approach confirmed the regulatory role of lncRNA BACE1-AS in amyloid generation, alcohol metabolism, and neuroinflammation. This report is the first to suggest the involvement of lncRNA BACE1-AS in alcohol-induced astrocytic amyloid generation and alcohol metabolism. These findings will aid in developing therapies targeting astrocyte-mediated neurological disorders and cognitive deficits in alcohol users.
根据国家药物使用与健康调查，10.5%的 12 岁及以上美国人患有酒精使用障碍，同时伴有多种神经紊乱。酒精介导的神经紊乱可能与类阿尔茨海默病病理有关，而后者尚未得到充分研究。我们假设酒精暴露会引起星形胶质细胞淀粉样变性，这可以通过在酒精使用障碍中观察到的神经紊乱来证实。在这项研究中，我们证明了星形胶质细胞暴露于乙醇会导致阿尔茨海默病标志物增加——淀粉样前体蛋白、Aβ1-42 和β-分泌酶；氧化应激标志物 4HNE；促炎细胞因子 TNF-α、IL1β 和 IL6；lncRNA BACE1-AS；以及酒精代谢酶——乙醇脱氢酶、乙醛脱氢酶-2 和细胞色素 P450 2E1。基因沉默方法证实了 lncRNA BACE1-AS 在淀粉样生成、酒精代谢和神经炎症中的调节作用。这是首次报道 lncRNA BACE1-AS 参与酒精诱导的星形胶质细胞淀粉样生成和酒精代谢。这些发现将有助于开发针对酒精使用者星形胶质细胞介导的神经紊乱和认知缺陷的治疗方法。
