氟西汀减少AD早期海马有髓神经纤维脱髓鞘的作用和机制

In the past, the studies on Alzheimer’s disease (AD) focused on the changes of neurons and synapses. Recently, we found that there was no neuron death, but there were the changes of the myelin sheaths and oligodendrocytes in the hippocampus of early AD. Therefore, the current project will focus on the myelin sheaths and oligodendrocytes in the hippocampus of early AD. We found that fluoxetine had the protective effects on the myelin sheaths in the hippocampus of depression rats. Whether have fluoxetine the protective effects on the myelin sheaths in the hippocampus of early transgenic AD mice? If fluoxetine have the protective effects, what are the structural bases and molecular mechanism of these effects? Until now, there have been no studies on these issues in the world. Therefore, we propose the hypothesis that in early AD, both the suppression of hippocampal oligodendrocyte apoptosis and the improvement of the myelination ability of the oligodendrocytes through the 5-HT1A receptor on the oligodendrocytes might be the important mechanism for the fluoxetine to reduce the demyelination. To verify this hypothesis, we would give the fluoxetine to the early transgenic AD mice, then explore the effects of fluoxetine reducing the demyelination of the myelinated fibers in the hippocampus of early transgenic AD mice and the structural bases and molecular mechanism of the effects using the behavior tests, immunohistochemistry techniques, transmission electron microscope techniques, stereological techniques and molecular biology methods. The results obtained in the present project will be very helpful for further understanding the structural and molecular bases of the protective effects of fluoxetine on the learning and memory in the early AD, which will provide very important theoretical and practical bases for exploring the new interventions to prevent and treat AD in the future.

过去对阿尔茨海默氏病（AD）的研究集中在神经元和突触改变上。我们近期发现，早期AD不存在海马神经元死亡，但存在有髓神经纤维脱髓鞘和少突胶质细胞的改变。因此本研究把目光投向早期AD海马有髓神经纤维髓鞘和少突胶质细胞。我们发现氟西汀对抑郁大鼠海马髓鞘有保护作用，那么氟西汀是否能在AD早期减少海马脱髓鞘？其作用的结构和分子机制为何？国内外尚未见报道。我们提出：在AD早期抑制海马少突胶质细胞凋亡和作用于早期AD海马少突胶质细胞5-HT1A受体来提高少突胶质细胞的髓鞘形成能力可能均是氟西汀减少早期AD海马脱髓鞘的重要机制。为验证此假设，我们拟对早期AD小鼠给予氟西汀，运用行为学、免疫组化、电镜、体视学和分子生物学等手段对氟西汀减少早期AD海马脱髓鞘的作用及作用的结构和分子机制进行探索，研究结果有助认识氟西汀改善早期AD学习记忆能力的结构和分子基础，对将来寻找防治AD的新手段具有重要的理论和实际意义。

过去对阿尔茨海默氏病（AD）的研究集中在神经元和突触改变上。我们近期发现，早期AD不存在海马神经元死亡，但存在有髓神经纤维脱髓鞘和少突胶质细胞的改变。因此，本研究把目光投向早期AD海马有髓神经纤维髓鞘和少突胶质细胞。我们发现氟西汀对抑郁大鼠海马髓鞘有保护作用，那么氟西汀是否能在AD早期减少海马脱髓鞘？其作用的结构和分子机制为何？国内外尚未见报道。本项目运用行为学、免疫组化、电镜、体视学和分子生物学等手段对氟西汀减少早期AD海马脱髓鞘的作用及作用的结构和分子机制进行探索，我们主要的研究发现是：氟西汀对早期APP/PS1转基因AD小鼠学习、空间记忆和工作记忆等认知功能均有显著的改善作用；氟西汀干预能够促进幼稚期少突胶质细胞分化成成熟的少突胶质细胞，这可能是氟西汀延缓AD进展的重要结构基础之一；氟西汀可以促进AD少突胶质细胞上5-HT1A受体的表达，抑制AD少突胶质细胞负性调节蛋白GSK3β的表达；氟西汀可能通过与少突胶质细胞5-HT1A结合，调节下游GSK3β的磷酸化，从而通过SOX10调控少突胶质细胞的分化，进一步提高少突胶质细胞形成髓鞘的能力；此外，氟西汀能够延缓早期APP/PS1转基因 AD小鼠大脑海马DG、CA1、CA2/3和内侧前额叶皮质内突触和突触蛋白的丢失；氟西汀还能够延缓早期APP/PS1转基因AD小鼠大脑内侧前额叶皮质的萎缩和神经元的丢失，并且可能是通过神经元上的5-HT4受体介导调控的。可见，氟西汀增高的5-HT在海马和内侧前额叶皮质有可能通过不同5-HT受体亚型介导的多种途径协同产生对抗AD病理过程的作用。这些研究结果为氟西汀改善早期AD学习记忆能力提供了重要的结构和分子基础，对将来寻找防治AD的新手段具有重要的理论和实际意义。