酒精摄入对脑β淀粉样蛋白及认知功能影响的研究

We have found that toxic dose of alcohol can cause the damage of learning and memory function, the overproduction and excessive expression of β amyloid protein 1-42 (Aβ1-42) and β amyloid protein 1-42 (Aβ1-40) in hippocampus and cortex. In addition, it has reported that low concentration of ethanol can protect primary cultured hippocampal neurons from the toxicity induced by Aβ. On these basis, the project will investigate the effect of different concentrations of alcohol on the secondary structure, aggregation behavior and the fiber formation of Aβ in vitro. Furthermore, this project will study the influence of long-term alcohol intake from low dose to the toxic dose on Aβ from C57BL/6 and the 2x transgenic mice for Alzheimer's disease (AD) C57BL/6-APP/PS1 mice in the brain, and on the correlation between Aβ and learning and memory function or the morphological changes of hippocampus and cortex tissues in vivo. The project especially attempts to reveal the effect of different doses of alcohol on Aβ aggregation process and Aβ deposition in hippocampus and cortex. Through the above research, it will clarify the role of the alcohol intake in the process and development of AD, whether alcohol intake is the inducing factor of AD or prevents the happening of AD, whether this effect is related to the amount of alcohol consumed per day. This research will provide a theoretical basis and scientific support for controlling the volume of alcohol intake every day to prevent AD.

在课题组发现中毒剂量的酒精能造成学习记忆的损伤、海马及皮层β淀粉样蛋白1-42（Aβ1-42）与β淀粉样蛋白1-40（Aβ1-40）的过量产生与表达以及文献报道低浓度乙醇对Aβ诱导的原代培养的海马神经细胞毒性有抑制作用的基础上，进一步研究不同浓度的酒精体外对Aβ聚集过程中二级结构、聚集特性与纤维形成的影响，体内长期摄入从低剂量到中毒剂量的酒精对C57BL/6小鼠与阿尔兹海默症（AD）APP /PS1 双转基因小鼠脑Aβ的影响及其与学习记忆、海马与皮层神经细胞组织形态学变化的相关性。在此基础上，重点研究不同酒精剂量对Aβ聚集过程与在海马与皮层沉积的影响，从而阐明酒精的摄入在AD的发生发展过程中所起的作用，是AD的诱发因素还是预防AD的发生，此作用是否与摄入酒精的量有关，为控制每天酒精的摄入量，预防老年痴呆提供可靠的理论参考和科学依据。

在课题组前期发现中毒剂量的酒精能造成学习记忆的损伤、海马及皮层β淀粉样蛋白1-42（Aβ1-42）与β淀粉样蛋白1-40（Aβ1-40）的过量产生与表达以及文献报道低浓度乙醇对Aβ诱导的原代培养的海马神经细胞毒性有抑制作用的基础上，本课题进一步研究了不同浓度的酒精体外对Aβ聚集过程中二级结构、聚集特性与纤维形成的影响，体内长期摄入从低到中毒剂量的酒精对C57BL/6小鼠与阿尔兹海默症（AD）APP/PS1双转基因小鼠脑Aβ的影响及其与学习记忆、海马与皮层神经细胞组织形态学变化的相关性。结果表明，不同酒精浓度对小鼠学习记忆能力、大脑氧化应激、Aβ的生成与沉积的影响不同。低浓度酒精一定程度上能起到抗氧化作用，减缓C57BL/6小鼠大脑氧化损伤，但是酒精浓度越高，体内氧化作用发生越剧烈，导致大脑氧化损伤越严重；低剂量的酒精摄入会减少C57BL/6正常小鼠、拮抗APP/PS1双转基因小鼠脑中Aβ的产生从而减少其沉积以降低神经毒性，维持正常的学习记忆功能，有利于AD的发生和减缓AD的进程发展，而过量酒精摄入则会增加Aβ在大脑的生成、加速其积累沉积，加重其病理特征和学习记忆功能的损伤，促进AD的发生与发展。此研究结果为阐明酒精摄入与AD之间的关系，是预防还是促进AD，为控制每天酒精的摄入量，预防老年痴呆提供了可靠的理论参考和实验依据。