建立阿尔茨海默病（AD）转基因猕猴模型

Alzheimer's disease (AD) is an age dependent neurodegenerative disorder, characterized by progressive patterns of cognitive and functional impairments. The literature indicates that neither has a complete description of the disease molecular pathways been elucidated, nor has an effective treatment been reported. It is obvious that the development of proper AD models is a key element in the disease's study. Given the fact that, up to now no non-human primates transgenic AD models have been developed, a transgenic AD rhesus monkey model seems highly required to fill up the gap. To develope a transgenic rhesus monkey AD model, we plan to inject Adeno-Associated Virus (AAV) that carries Familial Alzheimer's Disease (FAD) multi-mutant genes into the memory-related brain areas. Then use CANTAB（Cambridge Neuropsychological Test Automated Battery）system to evaluate mental functions of the AD model. Furthermore, we will conduct histopathology tests on the brain tissue for the further validation of the model. This non human primates AD model sharing high similarity with human patients will allows us to exclude interferences from the other brain areas when observing the expression of FAD genes within the memory-related regions. Such data would contribute to map the links between different functional brain areas and the related AD clinical symptoms.

阿尔茨海默病（AD）是排名第一的神经退行性疾病。AD病因仍不清楚，尚无有效诊疗方法。研发一种能体现AD病程的动物模型将为解决这一难题奠定良好基础。在我们已经成功建立甲醛诱导的新型猕猴AD模型的基础上，针对国际上高等级动物AD转基因模型建构领域的空白，拟开发转基因猕猴AD模型：采用局部微量注射的方法，向猕猴学习记忆密切相关的脑区通过AAV病毒转染APP-SWE/tau/PS1M146三突联合致病基因，然后利用国际通用的剑桥CANTAB猕猴认知测试系统，对成模动物进行多种记忆功能检测，并结合经典病理组织学进行病理验证，最终建立一种以模拟学习记忆障碍为核心症状的转基因猕猴AD模型。这种模型不仅具有与人高亲缘性的优势，还可以单独探索记忆功能脑区在AD致病基因的作用下产生的临床症状，解析不同脑区在AD致病过程中的作用。

阿兹海默病（AD）是排名第一的神经退行性疾病。AD病因仍不清楚，尚无有效诊疗方法。研发一种能体现AD病程的动物模型将为解决这一难题奠定良好基础。我们采用局部病毒注射的方法，向猕猴学习记忆功能密切相关的脑区注射AAV病毒，过表达FAD致病基因来进行建模。在建模过程中，我们相继测试了多种病毒载体，找到了最优的病毒载体以及摸索了一套脑区转基因的方法，开发了一套猕猴触屏认知测试系统及一套猕猴脑内活体荧光检测系统。通过对成模猕猴进行记忆功能检测，同时辅以经典病理组织学的验证，证实我们成功建立了转基因AD猕猴模型。这种模型不仅具有与人高亲缘性的优势，还可以单独探索记忆功能脑区在AD致病基因的作用下产生的临床症状，解析不同脑区在AD致病过程中的作用。