氟西汀通过5-HT系统多靶点对抗AD病理过程的作用和机制

The previous studies have indicated that fluoxetine could improve the cognitive function of AD. However, the underlying mechanism is not clear yet. Our previous studies have found that fluoxetine could improve the learning and memory abilities of APP/PS1 mice, reduce the active of GSK-3β in the hippocampus, increase the levels of BDNF and synapsin-1 in the hippocampus and delay the loss of the neurons in the dentate gyrus of APP/PS1 mice. In the present project, we will further study whether fluoxetine could inhibit the activity of GSK-3 through the 5-HT1AR, thus reducing Aβ and phosphorylated Tau protein in the hippocampus of AD mice. We will study whether fluoxetine could inhibit the activity of GSK-3β through the 5-HT1AR on the oligodendrocytes, thus promoting the proliferation and myelination of the oligodendrocytes and protecting the oligodendrocytes and myelin sheaths in the hippocampus of AD mice. We will study whether fluoxetine could induce the neurogenesis through the 5-HT4R on the neural precursor cells, thus increasing the neuronal precursors and newborn neurons and reducing the loss of the neurons in the hippocampus of AD mice. Moreover, we will study whether fluoxetine increases the level of BDNF through the 5-HT6R, thus protecting the NCAM2 and dendritic spines in the hippocampus of AD mice. The results obtained in the present project will be very helpful for further understanding the effects and mechanisms for the facts that fluoxetine confronted the pathological process of AD through multiple targets of 5-HT system, which will provide very important theoretical and practical bases for exploring the new interventions to prevent and treat AD in the future.

已有研究表明氟西汀能够改善AD的认知功能，但其机制仍不清楚。我们前期研究发现氟西汀能够改善APP/PS1小鼠的空间学习记忆能力，抑制其海马GSK-3β的活性，增加海马BDNF和突触蛋白-1的含量，减少海马齿状回神经元的丢失。本项目将进一步研究氟西汀是否通过AD海马5-HT1AR抑制GSK-3的活性而减少Aβ和磷酸化Tau蛋白的产生，并通过抑制GSK-3β的活性促进少突胶质细胞增殖和髓鞘形成，减少少突胶质细胞和髓鞘丢失；研究氟西汀是否通过AD海马多能干细胞5-HT4R增加神经前体细胞的数量，从而促进新生神经元的形成，减少神经元数目下降；研究氟西汀是否通过AD海马5-HT6R增加BDNF的表达而修复AD脑内NCAM2丢失造成的突触损伤，减少突触丢失。这些研究将对阐明氟西汀通过5-HT系统多靶点对抗AD病理过程的作用和机制，对寻找防治AD的新手段具有重要意义。

阿兹海默病（Alzheimer’s disease，AD）是最常见的痴呆症类型，是一种进行性加重的神经系统退行性疾病。目前AD的发病机制尚不清楚，仍然没有有效的治愈方法。近年来，通过五羟色胺（5-HT）系统干预AD受到广泛关注，其中氟西汀作为经典的选择性5-HT再摄取抑制剂也受到重视。然而，氟西汀是如何改善AD认知功能的还有待研究。因此，我们对APP/PS1转基因AD小鼠给予氟西汀干预，并运用行为学方法、体视学方法与免疫组化、免疫荧光相结合的方法以及分子生物学方法研究氟西汀通过5-HT系统多靶点对抗AD病理过程的作用和机制。我们主要的研究发现是：氟西汀能够改善APP/PS1转基因AD小鼠学习、认知和记忆功能；氟西汀能够减少APP/PS1转基因AD小鼠海马和前额叶皮质内磷酸化Tau蛋白、可溶性Aβ和老年斑；氟西汀能够延缓APP/PS1转基因AD小鼠海马和内侧前额叶皮质的萎缩；氟西汀能够促进APP/PS1转基因AD小鼠海马和内侧前额叶皮质内新生神经元的形成和存活，延缓神经元的丢失；氟西汀能够延缓APP/PS1转基因AD小鼠海马和内侧前额叶皮质内突触的丢失；氟西汀能够提高APP/PS1转基因AD小鼠海马和内侧前额叶皮质神经元上5-HT4R和5-HT1AR的含量，抑制GSK3β的表达和活性，这可能是氟西汀减轻转基因AD小鼠特征性病理改变，延缓转基因AD小鼠神经元和突触丢失的重要分子基础；氟西汀能够增加APP/PS1转基因AD小鼠海马内MBP和CNPase的表达量，促进髓鞘的修复；氟西汀能够促进APP/PS1转基因AD小鼠海马内幼稚期少突胶质细胞向成熟期少突胶质细胞分化，进而增加成熟少突胶质细胞的数量；氟西汀能够促进APP/PS1转基因AD小鼠原代少突胶质细胞上5-HT1A受体的表达，抑制GSK3β的表达，这可能氟西汀促进少突胶质细胞成熟，延缓少突胶质细胞丢失的重要分子基础。这些研究结果阐明了氟西汀对转基因AD小鼠海马和内侧前额叶皮质神经病理损伤的作用，并探讨了氟西汀通过5-HT系统多靶点对抗AD病理过程的分子机制，进一步认识氟西汀改善AD认知功能的机制，对将来寻找防治AD的新手段具有重要的意义。