基于自发性糖尿病老年食蟹猴阿尔茨海默病模型的建立和评估

项目名称： 基于自发性糖尿病老年食蟹猴阿尔茨海默病模型的建立和评估

项目编号： No.31472056

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 岳峰

作者单位： 首都医科大学

项目金额： 88万元

中文摘要： 缺乏能从病理特点和临床症状特征模拟人类阿尔茨海默（AD）病的动物模型是制约AD新药研发、早期诊断和转化医学研究的瓶颈所在。老化及糖尿病是AD的主要危险因素且与AD发病密切相关。本研究选用老年和自发性糖尿病老年食蟹猴，应用对流增强给药技术（CED）立体定向脑内（海马至额叶前回的脑区、内嗅区和颞叶皮质等）注射可溶性Aβ42寡聚体，旨在建立拟临床AD模型，其后间隔1-2月左右重复注射，造模前基线期和造模后动态评价认知行为和脑内β淀粉样蛋白（Aβ）斑块形成和相关生物标记物的变化，直到动物出现认知功能减退和/或出现Aβ斑块形成的。具体用延迟样品比对测试（DMTS）评价认知功能，检测脑脊液中Aβ40、Aβ42，P-tau 含量、18F-AV45-PET成像评价脑内Aβ斑块形成并结合脑组织活检分析Aβ斑块、Tau 病理的形成。此外，可初步研究糖尿病对Aβ病理形成的促进作用和机制。

中文关键词： 人类疾病动物模型；食蟹猴；2型糖尿病；β淀粉样蛋白；认知功能

英文摘要： Lacking of animal model of Alzheimer'disease (AD) that might be able to mimic the pathological and clinical characteristics of AD patients is the critical limitation for drug and therapeutical development, early diagnosis and translational medical research. Aging and Diabetes had been considered to be the main risk factors to be contributed to the β-amyloid formation.Convection-enhanced delivery technology was applied to stereotaxically intracranial injection (the area between the hippocampus and prefrontal, entorhinal and temporale lobe cortex ) of soluble Aβ42 oligomers to model the AD model, and then re-injection at 1-2 month interval, dynamic evaluation of cognitive function and β-amyloid plaque related biomarkers before and after post surgery modeling, until the appearance of impaired cognitive behavior and the β-amyloid related pathological evidences, meanwhile, the present study will estabolish a set of technical protocol for in vivo evaluation of AD model in non-human primates. The newly developed DMTS (Delayed-matching to Sample) testing panel will be used for cognition measurement, and the concentration of AD related specific biomarkers in cerebral spinal fluid includingβ40、Aβ42，P-tau will be dynamically analyzed, the formation and distribution of Aβplaque in the brain will be in vivo detected by a F18 combined specific radiopharmaceutical ligand AV45 uptake( 18F-AV45 PET imaging),and the immnohistopathological measurement of brain tissue collected by a biopsy. Moreover, the potential mechanism that diabetes and aging that could be predisposed to the formation of β-amyloid pathology and cognitive impairement would be preliminarily explored.

英文关键词： Animal model;Cynomolgus monkeys;T2DM;β Amyloid;Cognition