miR-124/Fpn信号通路在阿尔茨海默病神经元铁坏死及记忆障碍中的作用与机制

阿尔茨海默病（AD）最典型的临床症状是学习记忆障碍，神经元丢失在其中发挥重要作用。近年来，铁死亡在神经元死亡中的作用得到关注，但其在AD中作用不明。研究表明，AD脑内存在铁蓄积，脂质体氧化增强等与铁死亡密切相关的病变，我们发现AD模型小鼠海马神经元超微结构中呈现铁死亡特征性表型，生物信息分析也显示铁死亡相关差异表达基因在AD小鼠中高度富集；在AD小鼠模型和人脑组织中，铁离子唯一的泵出通道-膜铁转运蛋白（Fpn）含量明显下降，且受升高的miR-124在转录后调节。基于我们前期对miR-124在AD学习记忆障碍中的研究，我们推测，AD中miR-124/Fpn信号通路紊乱诱发了铁坏死，进而引起神经元丢失及学习记忆障碍。本项目将综合基因鼠杂交，生物信息分析，行为学，电生理等手段深入解析铁死亡现象对AD神经元丢失和学习记忆障碍的影响及其分子机制，为 AD 的治疗提供新的思路和药物靶点。

The most typical clinical symptom of Alzheimer's disease (AD) is learning and memory impairment, in which neuronal loss plays an important role. In recent years, the role of ferroptosis in neuron death has been paid attention, but its role in AD is unknown. Studies have shown that ferroptosis related pathological changes, such as iron accumulation, increased liposome oxidation can be found in AD brain. We found that AD model mouse hippocampal neuron ultrastructure showed characteristic phenotype of ferroptosis, and bioinfomatic analysis also showed ferroptosis-related differentially expressed genes are highly enriched in AD mice; in AD mouse models and human brain tissues, the only pump-out channel of iron ions, the membrane iron transporter (Fpn), was significantly reduced, and can be regulated by the elevated miR-124 post-transcriptionally. Based on our previous research on miR-124 in AD learning and memory disorders, we speculate that the disturbance of the miR-124 / Fpn signaling pathway in AD induces ferroptosis, which in turn causes neuron loss and learning and memory disorders. This project will comprehensively analyze the effects of ferroptosis on AD neurons loss and learning and memory disorders and their molecular mechanisms through comprehensive genetic mouse hybridization, biological information analysis, behavioral science, electrophysiology and other means, providing new ideas and drugs for the treatment of AD Target.