Nogo-66/NgR通路介导的神经炎症在阿尔茨海默氏病发病机制中的作用研究

Alzheimer's disease (AD) is a common neurodegenerative disease with neuropathological hallmarks of intracellular neurofibrillary tangles and extracellular senile plaque composed primarily of amyloid β-peptides (Aβ). Neuroinflammation has been highlighted as one possible key contributing factor to AD. The classic hallmarks of neuroinflammation, such as activated microglia, activated astrocyte and increased cytokine expression, are all observed in the tissue of AD patients and transgenic AD mice. Nogo receptor (NgR) is the receptor of myelin-associated inhibitor Nogo-66. NgR expressed on the neuron participates not only in arresting neurite outgrowth but also in Aβ pathology. NgR also expresses on the microglia and Nogo-66/NgR signaling pathway mediates neuroinflammation via microglia, but the role of neuroinflammation mediated by Nogo-66/NgR in the AD pathogenesis remains unclear. Therefore, this project will explore the role of neuroinflammation mediated by Nogo-66/NgR signaling pathway in the AD pathogenesis by use of molecular technology, cellular technology and Alzheimer's transgenic mice, etc. The research contents about this project will include three parts: (1) The role of Nogo-66/NgR pathway on the mediating microglia adhesion, migration, Aβ uptake and Aβ degradation; (2) The influences of neuroinflammation mediated by Nogo-66/NgR pathway on the Aβ production, tau hyperphosphorylation and Aβ aggregation; (3) The effects of blockade of Nogo-66/NgR pathway on the Aβ plaque and spatial memory in Alzheimer's transgenic mice. This study will help to clarify the relationship between Nogo-66/NgR, microglia, neuroinflammation and AD and highlight the role of neuroinflammation in Alzheimer's disease. The Nogo-66/NgR will provide a novel site for modifying the course of AD and become to be potential target for drug development in treatment AD.

阿尔茨海默病（AD）是一种神经退行性疾病，神经炎症在AD的发病机制中扮演重要角色。NgR是神经生长抑制分子Nogo-66的受体，小胶质细胞的Nogo-66/NgR通路介导了神经炎症， 但Nogo-66/NgR通路介导的神经炎症是否参与AD的发病机制，国内外尚无相关报道。所以，本课题将利用分子生物学、细胞生物学和转基因动物等技术，从分子、细胞和整体动物多层面，探讨小胶质细胞Nogo-66/NgR通路介导的神经炎症在AD发病机制中的作用， 内容包括（1）Nogo-66/NgR通路介导小胶质细胞对Aβ的粘附、迁移、吞噬和降解作用；（2）Nogo-66/NgR通路介导的炎症环境对神经元生成Aβ、tau蛋白的磷酸化、Aβ聚集的影响；（3）Nogo-66/NgR通路阻断后对转基因AD小鼠的Aβ沉积、空间记忆的影响。本课题的完成将为以后针对Nogo-66/NgR通路为靶点的AD药物开发提供新的思路。

阿尔茨海默病（AD）的病理特征是Aβ沉积和神经纤维缠结，神经炎症在AD发病过程中发挥着重要的作用。我们前期的研究发现小胶质细胞的 Nogo-66/NgR 通路介导了神经炎症， 但 Nogo-66/NgR通路介导的神经炎症是否参与 AD 的发病机制，国内外尚无相关报道。本课题利用分子生物学、细胞生物学和转基因动物模型等技术手段，探讨Nogo/NgR通路介导的神经炎症在AD发病过程中的作用及可能的分子机制。经过4年的研究，我们发现：（1）阻断Nogo-66/NgR 通路影响小胶质细胞Rho GTPase蛋白的活性，导致细胞骨架重构，从而增加介导小胶质细胞对 Aβ的粘附、迁移、吞噬和降解作用。（2）阻断Nogo-66/NgR通路或慢病毒干扰NgR表达，可减轻通路诱导的神经炎症环境，从而降低神经元的Aβ产生、聚集和tau蛋白的过度磷酸化；（3）Nogo-66/NgR 通路阻断后可减轻APP/PS1小鼠脑内的神经炎症环境，降低转基因 APP/PS1 小鼠的 Aβ沉积和tau蛋白磷酸化，并改善小鼠学习和空间记忆。以上结果提示Nogo-66/NgR 通路介导了小胶质细胞对 Aβ的粘附、迁移、吞噬和降解作用；Nogo-66/NgR通路诱导的神经炎症环境促进APP/PS1小鼠脑内Aβ沉积和tau蛋白的磷酸化以及小鼠的学习和记忆。Nogo-66/NgR通路在AD的发病机制中起着很重要的作用，它可能成为AD治疗药物的重要靶点， 为今后药物开发提供了新的思路。本课题共发表18篇文章，13篇SCI，5篇核心期刊，影响因子累计有48。课题组参加了3次国际会议，2次国内学术会议，会议论文有4篇。课题组获得教育部科技进步二等奖.课题期间培养硕士研究生8名，博士研究生5名，本科实习生12名。