3MST-H2S生成途径在阿尔茨海默病中的作用研究

Alzheimer's disease(AD) stands increasingly prominent position in the disease spectrum of the elderly, but its pathogenesis is still fully unknown, and the ideal treatment drugs for AD are unavailable yet. Hence it is very important to further explore the pathogenesis of AD, and quest for effective AD drug treatment of new strategy or new target. Hydrogen sulfide (H2S) is recently recognized to be served as the third gaseous transmitter alongside nitric oxide and carbon monoxide. It is reported by a series of researches that H2S is probably involved in AD pathogenesis, but direct evidence is still unavailable till now. Therefore the present study is designed to firstly investigate the relation between H2S levels in hippocampus, the learning and memory center, and AD pathogenesis using amyloid precursor protein （APP）/presenilin 1（PS1）doubled-transgenic mice. On the basis of the results，the model with APP/PS1 doubled-transgenic and conditinal 3-mercaptopyruvate sulfurtransferase (3MST) of brain gene-knockout mice is applied to explore the mechanisms that H2S levels in hippocampus decrease in the process of AD pathogenesis. At the same time, the possible intervention effect of exogenous supplementation of H2S on AD pathogenesis is also researched using the above two models. Finally, mechanism of action of H2S against AD is further detected in primary cultured hippocampus neuron injury model induced by abata 25-35. The present study is aimed to investigate the important effects of 3MST-H2S producing pathway on pathogenesis of AD, and to provide theoretical basis for the following research and development of treatment drugs for AD aiming to this pathway.

阿尔茨海默病(AD)在老年人疾病谱中的地位日益突出，其发病机制未完全明了，也尚无理想的治疗药物，故进一步探索AD发病机制，寻找有效的AD药物治疗新策略、新靶点具有重要意义。近年来，硫化氢被认为是继一氧化氮和一氧化碳后的第三类气体信号分子，系列研究发现其可能参与了AD的发病过程，但迄今尚无直接证据。因此，本项目首先通过APP/PS1双转基因AD小鼠模型，研究学习记忆中枢海马硫化氢水平与AD发病的关系；在此基础上，通过APP/PS1双转基因合并脑条件性3MST基因缺陷小鼠模型，研究在AD发病过程中海马硫化氢水平降低的机制；同时通过以上两种模型，探索外源性补充硫化氢对AD发病可能的干预作用；最后通过淀粉样蛋白1-40片段诱导的原代培养海马神经元损伤模型，深入研究硫化氢抗AD的作用机制。本项目旨在探索3MST-硫化氢生成途径在AD发病中的重要作用，并为后续研发针对该途径的AD治疗药物提供理论依据。

阿尔茨海默病(AD)在老年人疾病谱中的地位日益突出，其发病机制未完全明了，.也尚无理想的治疗药物，故进一步探索AD 发病机制，寻找有效的AD 药物治疗新策略、新靶点具有重要意义。近年来，硫化氢被认为是继一氧化氮和一氧化碳后的第三类气体信号分子，系列研究发现其可能参与了AD 的发病过程，但迄今尚无直接证据。因此，本项目首先通过淀粉样蛋白诱导的大鼠学习记忆减退模型、APP/PS1 双转基因AD 小鼠模型，研究学习记忆中枢海马硫化氢水平与AD 发病的关系；在此基础上，通过APP/PS1 双转基因合并脑条件性3MST 基因缺陷小鼠模型，研究在AD 发病过程中海马硫化氢水平降低的机制；同时通过以上两种模型，探索外源性补充硫化氢对AD 发病可能的干预作用；最后通过淀粉样蛋白1-40 片段诱导的原代培养海马神经元损伤模型，深入研究硫化氢抗AD 的作用机制。结果发现：（1）NaHS（硫化氢的供体）可明显减轻Aβ1-42所致的大鼠学习记忆减退及海马神经元的形态学损伤，增加存活神经元，其机制可能与阻遏CBS-H2S和3MST-H2S合成途径的降低从而维持海马H2S水平。（2）H2S减轻AD小鼠学习记忆减退作用和减少老年斑的数量及阻遏存活神经元数量减少，其机制可能与抑制APP-Aβ产生途径、上调H2S生成和诱导Nrf2信号通路有关。（3）维持海马硫化氢水平可阻遏小鼠学习记忆减退。该研究为表明3MST-硫化氢生成途径在AD 发病中的重要作用，为后续研发针对该途径的AD 治疗药物提供理论了依据。