乙醛，乙醇在体内的有毒代谢产物，是介导过量摄入酒精饮料导致大脑组织损伤和认知功能破坏的重要因素。乙醛在体内代谢清除主要通过乙醛脱氢酶2。由于个体摄入过多乙醇，或乙醛脱氢酶基因缺陷，在大脑生成的乙醛将积累并产生神经毒性，成为促进神经退行性疾病发生的危险因素。研究发现，大量饮酒可提早阿尔茨海默症(AD)发病年龄2-3年，同时乙醛脱氢酶基因缺陷增加迟发性AD的患病风险。 但目前乙醛神经毒性的准确分子机制及其如何影响AD的病理发展尚不清楚。 本项目拟利用神经细胞及转基因小鼠模型对乙醛神经毒性的分子机制进行详细分析，特别是乙醛对神经细胞的氧化还原状态、细胞凋亡/生存信号，以及乙醛对AD的重要病理特征Abeta生成和聚合及tau蛋白磷酸化的影响。通过本项研究，希望能够进一步明确乙醛神经毒性的分子机制以及乙醛诱导的神经毒性对AD病理特征形成的作用，并为探讨如何对其进行抑制打下理论基础。

Acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damage and cognitive dysfunction induced by long term alcohol misuse. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in metabolism of acetaldehyde to less toxic acetate. Local accumulation of acetaldehyde in brain due to over consumption of alcohol beverages or ALDH2 gene defect causes neurotoxicity and is a risk factor for neurodegenerative diseases. It has been reported that ALDH2 deficiency increases the risk for late-onset Alzheimer's disease (AD), while heavy drinking is associated with an earlier onset of AD by 2-3 years. However, the exact molecular mechanisms of acetaldehyde-induced neurotoxicity are unclear, and we know little about how acetaldehyde-induced neurotoxicity affects the pathogenesis of AD. In this project，we will study the molecular mechanisms of acetaldehyde-induced neurotoxicity, specifically, the effect of acetaldehyde on redox status, apoptotic and survival signaling in neuronal cells, and the impact of acetaldehyde on major AD pathological events including the production and aggregation of beta-amyloid and the phosphorylation of tau protein. The proposed study will further our understanding on acetaldehyde-mediated neurotoxicity and its effects on AD pathological development, and provide insights for future exploration of strategies to reduce the neurotoxicity induced by acetaldehyde or alcohol misuse.