Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation

作者：Veronika Brezáni, Radhika Joshi, Martí Ortega‐Ribera, Prashanth Thevkar Nagesh, Veronika Brezáni, Adam Zivny, Evelyn A. Kurt‐Jones, Douglas T. Golenbock, Gyöngyi Szabó · 发表于：Journal of Neuroinflammation · 年份：2025 · DOI：10.1186/s12974-025-03501-8 · 被引用次数：7 · 研究领域：Alcohol Consumption and Health Effects、Neuroinflammation and Neurodegeneration Mechanisms、Alcoholism and Thiamine Deficiency

BACKGROUND: Alcohol use disorder (AUD) has been associated with Alzheimer's disease (AD) and dementia, yet the underlying mechanisms and specific role of ethanol in AD progression remain poorly understood. Neuroinflammation has emerged as a key contributor to both AD pathogenesis and ethanol-induced brain damage. Activation of innate immune cells and signaling pathways, in particular NLRP3 inflammasome, plays a pivotal role in both AD and ethanol-induced inflammation. Thus, we postulated that excessive ethanol consumption could contribute to AD progression via amplified neuroinflammation. METHODS: The 12-15-month-old WT and APP/PS1 mice received water or ethanol (3.5 g/kg) binge every alternate day for a period of one month. The effects of ethanol on amyloid pathology, microglia and astrocyte activation, and NLRP3 inflammasome activation were evaluated in the mouse brains. The effect of ethanol and amyloid β on NLRP3 inflammasome signaling was further studied in primary glial cells. RESULTS: In this study, we show that repeated ethanol binges aggravate the amyloid pathology and plaque burden in the hippocampus of APP/PS1 mice. Furthermore, we demonstrate the additive effect of ethanol administration on NLRP3 inflammasome activation, IL-1β release, and ASC aggregation in the brains of APP/PS1 mice and primary glia cultures. Our study also reveals a strong astrocyte activation by ethanol in the hippocampus of APP/PS1 mice as demonstrated by significantly increased GFAP and ALDH...