LINGO-1对早期AD海马少突胶质细胞和髓鞘损伤的影响和机制

Previous studies have shown that LINGO-1 protein may play an important role in early AD. Our previous study found that LINGO - 1 protein was expressed in a high level in the hippocampus during early AD mice. Meanwhile, we found the marked loss of oligodendrocytes and the damages of myelin sheaths in the hippocampus during early AD mice. Therefore, we hypothesized that LINGO-1 protein may be involved in the damages of oligodendrocytes and myelin sheaths in the hippocampus during early AD, which might lead to memory impairments and cognitive decline. However, these effects and mechanisms are still unexplored. We speculated that the high level of LINGO - 1 protein in the hippocampus might induce the phosphorylation of GSK-3β and Radixin through the signaling pathways of RohA/ROCK, thus inhibiting the proliferation, differentiation, maturity and myelination of the oligodendrocytes in the hippocampus in the early stage of AD mice. To verify this hypothesis, we will study the effects and mechanism of LINGO-1 antagonist on the damages of oligdendroctes and myelin sheaths in the hippocampus and the memory and cognitive function in the early stage of AD mice using a series of behavioral tests, immunohistochemical methods, electron microscope, stereological methods and molecular biological methods. The results obtained in the present project will provide very important theoretical and practical bases for exploring the new interventions to prevent and treat AD in the future.

以往研究显示LINGO-1可能在早期AD中扮演着重要角色。我们前期研究发现学习记忆能力下降初期的AD小鼠海马LINGO-1高表达的同时，其海马内存在少突胶质细胞减少和髓鞘丢失，推测LINGO-1可能参与了早期AD海马少突胶质细胞和髓鞘损伤过程，导致记忆和认知功能障碍。然而，该作用及机制还有待研究。我们提出海马LINGO-1高表达可能促进早期AD海马RhoA/ROCK信号通路过度激活，导致糖原合成酶激酶-3β和根蛋白的过度磷酸化，从而抑制少突胶质细胞增殖、分化和成熟以及髓鞘形成，造成海马少突胶质细胞和髓鞘的损伤。为验证这一假设，我们拟对早期AD小鼠给予LINGO-1拮抗剂拮抗海马LINGO-1的作用，运用行为学、免疫组化、电镜、体视学和分子生物学等手段探索LINGO-1对早期AD海马少突胶质细胞和髓鞘损伤以及记忆和认知障碍的作用及机制，研究结果对将来寻找防治AD的新靶点和新手段具有重要意义。

LINGO-1是一种神经生长抑制因子，在阿尔兹海默症（Alzheimer’s disease，AD）模型小鼠和AD患者中均呈现显著高表达的情况，然而LINGO-1在AD发病中的作用仍有待研究。本课题以海马为例，研究海马内LINGO-1对APP/PS1小鼠海马依赖的空间学习和记忆能力以及海马内少突胶质细胞的影响，并以LINGO-1为干预靶点，探讨拮抗海马内LINGO-1能否改善APP/PS1小鼠海马依赖的空间学习和记忆能力并逆转海马少突胶质细胞的异常改变。我们研究发现：1. 海马LINGO-1过表达可能导致海马依赖的空间学习和记忆能力损伤，而抑制海马内LINGO-1的异常高表达能够逆转AD小鼠海马依赖的空间学习和记忆功能的损伤，提示海马LINGO-1介导了AD小鼠海马依赖的空间学习和记忆能力的损伤。2. LINGO-1及其下游信号通路RhoA/ROCK2不仅通过GSK3β负性调节APP/PS1小鼠海马少突胶质细胞的分化成熟，而且还参与了少突胶质细胞增殖分化成熟相关基因的调控，进而导致海马内少突胶质细胞的异常改变，提示LINGO-1在AD小鼠海马少突胶质细胞的异常改变中扮演着重要角色。3. 以LINGO-1为干预靶点干预AD能够有效修复AD小鼠的空间学习和记忆损伤，促进其海马内少突胶质细胞的增殖分化成熟，该作用的机制可能是抗LINGO-1抗体在抑制LINGO-1后进一步激活了Wnt/β-catenin信号通路，进而促进少突胶质细胞增殖分化成熟。这些研究结果表明海马LINGO-1在AD发病中扮演着重要角色，抗LINGO-1抗体能够有效改善AD的认知功能，这可能与LINGO-1对少突胶质细胞的调控作用密切相关，少突胶质细胞有望成为AD防治的关键靶点之一，对进一步探寻AD发病机制和防治手段具有重要价值。