单核细胞源resistin介导的成年脑微血管重构在阿尔茨海默病发病中的作用及机制研究

Alzheimer's disease (AD), also known as senile dementia, is a chronic neurodegenerative disease that usually starts slowly and gets worse over time. However，the pathogenesis of AD has not been fully understood. We found previously that CD14+CD16- peripheral monocytes of AD patients overexpress resistin. To find out the biological effect of resistin playing in adult brain, we developed a transgenic mouse (Mresistin+) overexpressing human resistin specifically in monocytes. It was showed that resistin resulted in a series of brain microvascular remodeling changes in Mresistin+, such as a reduction in adult mouse brain microvascular branches, a decrease in microvascular density which is an age-dependent accelerated progression. Further, we found that accompanying with the age-dependent accelerated progression of the brain microvascular remodeling in Mresistin+/APP/PS1 mouse, the Aβ deposition was increased and the cognitive impairment was aggrieved. Based on these results, our research aims to find out the mechanism of resistin mediated brain microvascular remodeling. Furthermore, the mechanism of resistin-mediated microvascular remodeling in Aβ metabolism and cognitive impairment in AD patients will be investigated by combining with the dynamic expression of resistin in monocytes before and after AD dementia. It will be illuminated whether peripheral monocytes induce AD pathogenesis by remodeling adult brain microvascular structure and whether monocyte derived resistin is a potential risk factor of AD.

阿尔茨海默病（AD）又名老年痴呆症，其发病机制仍未完全明了。我们前期发现：AD患者外周血单核细胞（CD14+CD16-）过表达resistin，在针对此构建的单核细胞特异性高表达人resistin的转基因小鼠（Mresistin+小鼠）中发现，resistin导致了成年小鼠脑微血管分支减少、密度降低并且呈增龄性加重的血管重构性改变；在Mresistin+/APP/PS1杂交小鼠中观察到随脑微血管重构增龄性加重，脑内Aβ沉积逐渐增加、认知障碍加重。本课题拟在此基础上，探讨resistin介导脑微血管重构的机制，结合临床AD患者痴呆前后单核细胞中resistin的动态表达，研究resistin介导的脑微血管重构在AD脑内Aβ代谢及认知障碍中的作用机制。本课题可望获得“外周血单核细胞通过控制成年脑微血管结构而诱发AD发病”结论，提出过表达的单核细胞源resistin是AD发病潜在风险因子新概念。

文摘中要 (对项目的背景、主要研究内容、重要结果、关键数据及其科学意义等做简单.阿尔茨海默病(AD)患者除脑内有Aβ沉积之外,超过90%的AD患者同时存在脑微血管分支减少和密度下降等病理改变,但其机制尚不清楚。本项目基于前期观察到的AD患者单核细胞过表达resistin及自己构建的单核细胞特异性高表达人resistin转基因小鼠，在观察到resistin转基因小鼠有脑微血管密度降低等重构性改变基础上，进一步探讨了单核细胞源resistin 导致小鼠脑微血管重构改变的机制及其与Aβ沉积和痴呆的关系。研究结果表明：单核细胞源resistin通过诱导脑微血管内皮细胞Claudin5表达和内皮细胞衰老双重途径调控脑微血管内皮细胞重构；AD小鼠脑内Aβ沉积增加与单核细胞过表达resistin诱发的脑微血管密度减少所致的Aβ清除障碍密切相关；单核细胞源resistin减少小鼠海马神经干细胞数量参与到AD痴呆过程。本项工作在一定程度上回答了AD患者脑微血管分支减少密度下降病理改变机制及其在AD病变中的作用,揭示出外周血单核细胞源resistin是AD微血管病变的潜在风险因子。