阿尔兹海默病（AD）猕猴自发模型的筛选鉴定

Alzheimer’s disease (AD) is regarded as the most common neurodegenerative disease in human. The molecular mechanism of AD is poorly understood and currently there is no effective treatment. With an aging population and the associated increased social and economic burden on society, China great needs urgently to better understand and effectively treat Alzheimer’s disease. Obviously the development of proper AD models is a key element in the study of AD, especially a spontaneous model that could mimic the natural physiopathologic aspects of human AD. Thus, in this study, we attempts to screen naturally occurring (spontaneous) AD monkeys as a model of human AD, using a variety of techniques based on the successfully established new formaldehyde-induced AD macaque model and the rich resources of elderly rhesus monkeys in Kunming institute of Zoology. Cerebrospinal fluid (CSF) levels of AD biomarkers (Aβ，phosphorylated tau etc.) as well as brain imaging will be employed to screen potential AD monkeys. Then cognitive ability (working memory) will be further assessed with CANTAB and WGTA. Finally, postmortem histological evaluations will be used to validate the AD pathologic changes of the monkeys. Our previous work revealed that CSF Aβ42 level increased in the aged monkeys. Furthermore, massive intracellular Aβ depositions and extracellular plaques were observed in the brain of a natural died old macaques. These preliminary results indicate that, as evolutionary neighbor of human, monkeys may spontaneously develop AD-like pathology and behavior changes during aging. At the same time, these findings also laid a good foundation for this project.

AD疾病机制研究和有效预防治疗药物研发已经成为全球性的公共卫生问题。为了解决这一难题，建立能很好模拟人类AD发病过程和临床特点的自发猕猴AD模型是一个重要途径。因此，本研究将利用中国科学院昆明动物研究所丰富的老年猕猴资源和成熟的行为学训练设备和范式，采用多种技术手段系统的对老年化猕猴进行筛选：首先通过脑脊液AD标志物检测及脑影像学检测初步筛选出一批潜在的AD猕猴，然后进一步对这些初筛出来的老年猴进行认知能力、AD病理指标检测，最终从老年猕猴中筛选出自然发生的猕猴AD模型。我们根据这一思路进行的预实验表明：猕猴脑脊液中Aβ42的含量随年龄升高上升，且自然死亡老年猕猴脑片中存在大量胞内Aβ沉积和Aβ plaque。这些与AD密切相关的经典病理结果提示我们，随着老年化，猕猴很有可能自发产生类似于人类AD患者的个体。同时，也为本项目的完成奠定了良好的工作和技术基础。

阿尔茨海默病 (Alzheimer's Disease, AD) 是人类最常见的神经退行性疾病，目前病因不明，治疗无效，也缺乏有效的预防措施。猕猴在进化上与人类关系密切，大脑结构与人类相似，又有着复杂的行为和认知能力，是很好的人类神经退行性疾病的研究对象。更重要的是猕猴也会表现出与人类相似的衰老和神经退化特征，如果猕猴也能自发地罹患AD，那么也许猕猴将成为攻克AD路上连接科学研究和临床转化之间的重要桥梁，为彻底解决AD问题奠定基础。尽管越来越多的证据表明在老年猕猴中存在不同程度的AD样病理特征，但猕猴能否自发地患有AD仍然是一个颇具争议的话题，因此，本研究的目的就是筛选和鉴定出自发患有AD的老年猕猴。在本研究中，我们发现随着猕猴年龄的增长，其脑脊液中的Aβ40和Aβ42浓度都有显著下降的趋势，而甲醛浓度则显著升高，我们还发现脑脊液中甲醛水平的升高与Aβ40和Aβ42浓度只在老年组猕猴中有显著负相关。随后，我们选取十只老年猕猴作为研究对象，对其进行行为学测试，发现十只老年猕猴中有三只表现出区别于正常老年猴的空间工作记忆障碍和面对环境刺激表现出低反应性的行为异常。于是我们对这些认知障碍的老年猕猴大脑中进行AD相关的病理检测，发现有两只认知障碍猕猴的大脑中不仅同时出现不同程度的老年斑和神经纤维缠结，而且还有明显的细胞凋亡。本研究是首次严格参照人类AD诊断标准，筛选出两只自发AD的猕猴，这一结果不但证明AD并不是人类特有的疾病，和人类近缘的非人灵长类动物可能也会自发AD；还说明猕猴将在AD的造模、寻找早期诊断生物标志物和了解AD病因学方面具有很大的应用潜力。