半乳糖凝集素- 1改善小胶质细胞活化失衡缓解阿尔茨海默病变的机制研究

Although the cause for Alzheimer's disease (AD) is still unclear, recent findings have indicated that inflammation in central nervous system effectively involved in the onset of the disease. The effect of anti-inflammation or pro-inflammation from activated microglia is the central factor in controlling inflammation develops in brain. In the present study, we hypothesized that the balance between inflammation and anti-inflamation cytokines in the brain has been broken (associated disequilibration) is the vital factor in AD pathology progress, and the imbalance of activated microglia in anti-inflammation and pro-inflammation function (activation disequilibration) is the trigger for "associated disequilibration". To demonstrate these hypotheses, the AD rat model in different phase has been used, and the effect of galectin-1 on AD pathology character, microglia activating, the difference expression in pro-inflammation and anti-inflammation factor in in vivo and in vitro has been explored, in aim to demonstrate the relations between "associated disequilibration" and "activation disequilibration" and the role of imbalance in AD. The meanings of the study are 1. to verify "the imbalance in microglia activation induce associated disequilibration" play a key role in AD; 2. to confirm the effect of galectin-1 on attenuating activation disequilibration which benefit to AD prevention and provide new insight and target in AD treatment.

中枢神经系统炎症是诱导神经元损伤，促发阿尔茨海默病（AD）的重要因素。而小胶质细胞激活后表现出抗炎或促炎效应则是控制中枢炎症发展方向的中心环节。本项目提出：脑内抗炎与促炎因子动态平衡失调（联动失衡）可能是导致AD中枢炎症发展的关键因素，而活化的小胶质细胞抗炎与促炎功能平衡失调（活化失衡）又是造成"联动失衡"的主要原因。因此，本研究拟复制不同时程AD大鼠模型，并采用具有细胞分化调控作用的半乳糖凝集素- 1（galectin-1，gal-1）进行体内外干预，以认知记忆，AD病理改变，小胶质细胞激活功能变化，抗炎与促炎信号表达差异为考察点，探讨"活化失衡"与"联动失衡"的内在关联，揭示平衡失调在AD发生中的作用。本研究意义在于：1.证明小胶质细胞"活化失衡"诱导"联动失衡"是导致神经元损伤诱发AD的重要因素；2. 明确gal-1改善"活化失衡"，减轻AD病变的作用，为AD防治提供新思路和新靶点。

阿尔茨海默病（Alzheimer's disease， AD）是一种发生于老年期或老年前期的慢性神经退行性疾病。研究认为：神经炎症反应是促发AD的重要因素，而小胶质细胞则在中枢神经炎症发生发展中起着主导性作用。生理状况下，小胶质细胞处于静息态，在β淀粉样蛋白 (β-amyloid protein，Aβ) 沉积、颅脑损伤等病理因素刺激下，小胶质细胞迅速由静息态转为激活态而活化。研究发现：激活的小胶质细胞存在功能相反的活化态：“经典活化态（classically-activated，M1）”和 “选择活化态（alternatively-activated，M2）”。M1小胶质细胞释放白细胞介素-1β, 肿瘤坏死因子-α等炎症因子促进细胞损伤，而M2小胶质细胞释放脑源性神经营养因子，白细胞介素-10等抗炎因子促进细胞修复存活。基于对小胶质细胞激活态差异的认识，本项目提出：脑内抗炎与促炎效应动态平衡失调可能是导致AD中枢炎症发展的关键因素，而小胶质细胞向M1型激活转化增多导致M1型细胞功能占优，M2型细胞作用弱化又是造成抗炎-促炎失衡诱导AD 发生的重要原因。. 本项目以Aβ侧脑室注射诱导动物AD模型，并实施半乳糖凝集素- 1（galectin-1，Gal-1）干预，实验发现：1）小胶质细胞激活改变参予了AD发展，伴随AD的疾病时间进程，M1型小胶质细胞相对增多，而M2型小胶质细胞相对减少，出现M1-M2活化的失衡，动物也伴随出现记忆能力进行性降低、神经元凋亡丢失等AD病理变化；2）伴随AD疾病发展，脑内促炎因子逐渐增加，而抗炎因子释放减少，表现明显的中枢炎症状态；3）Gal-1干预可以部分缓解小胶质细胞激活失衡，改善脑内抗炎-促炎的不平衡状况，并缓解Aβ诱导的AD样病变；4）JNK信号通路参予Gal-1对小胶质细胞激活的调控。. 项目明确了：1）小胶质细胞活化失衡与中枢抗炎-促炎动态平衡失调内在关联，小胶质细胞激活转化失衡，诱导脑内抗炎-促炎平衡失调是促进AD的重要因素；2）Gal-1干预能够改善AD病理，其作用与Gal-1调控小胶质细胞激活，改善中枢抗炎-促炎失衡有关。