Student Catholic University of Korea Catholic university of Korea, Republic of Korea
Abstract: Ethanol exposure is a widely recognized environmental factor that disrupts neuronal function and has been implicated in neurodegeneration processes. The COVID-19 pandemic has further exacerbated concerns regarding alcohol consumption, with studies reporting increased alcohol use as a response to heightened psychological distress and social isolation. Given the chronic risks associated with excessive alcohol intake, understanding its impact on the nervous system is critical. Chronic alcohol consumption has been associated with cognitive decline and an increase of Alzheimer's diseases (AD), yet the precise mechanisms remain incompletely understood. In particular, the effects of ethanol on neuronal maturation, synaptic integrity, and amyloid-beta (Aβ) accumulation in human neurons have not been fully defined. This study utilizes human iPSC-derived cortical neurons and three-dimensional cerebral organoid models to investigate the impact of ethanol exposure on key neurobiological mechanisms. We first confirmed that ethanol exposure at physiologically relevant concentrations dose not compromise neuronal viability, as assessed by CCK-8 assays and Ki67 expression. However, ethanol exposure led to a significant reduction in neuronal maturation markers, including MAP2, FOXG1, TBR1 and FZD9, at both the protein and transcriptional levels Additionally, ethanol exposure resulted in increased Aβ accumulation, accompanied by upregulation of BACE1 and downregulation of ADAM10, suggesting ethanol-mediated alterations in amyloidogenic processing. These effects were further validated in three-dimensional spheroid and organoid models, where ethanol exposure impaired neurite outgrowth, reduced dendritic complexity, and exacerbated Aβ deposition. Together, these findings provide evidence that ethanol disrupts neuronal differentiation and synaptic stability while promoting amyloidogenic pathways, confirming its potential role in accelerating neurodegeneration. By integrating two- and three- dimensional human neuronal models, this study offers new insights into the molecular consequences of ethanol exposure, highlighting its relevance in neurodegenerative disease progression and the need for further research into alcohol-related cognitive decline.
Funding Source: This work was supported by the National Research Foundation of Korea (NRF) and ministries including Science and ICT, Trade, Industry and Energy, Health & Welfare, and Food and Drug Safety (RS-2023-KH142779, RS-2024-00512348).
