Discovery Preclinical and Early Development Neuroscience, Merck & Co., Inc., Kenilworth, NJ, USA.
Genetics and Pharmacogenomics, Merck & Co., Inc., Kenilworth, NJ, USA.
Neurobiol Aging. 2018 Apr;64:92-106. doi: 10.1016/j.neurobiolaging.2017.12.011. Epub 2017 Dec 20.
While many preclinical models of Alzheimer's disease (AD) have been reported, none fully recapitulate the disease. In an effort to identify an appropriate preclinical disease model, we characterized age-related changes in 2 higher order species, the African green monkey (AGM) and the rhesus macaque. Gene expression profiles in the dorsolateral prefrontal cortex and the visual cortex showed age-related changes in AGMs that are strikingly reminiscent of AD, whereas aged rhesus were most similar to healthy elderly humans. Biochemically, age-related changes in AGM cerebrospinal fluid levels of tau, phospho-tau, and amyloid beta were consistent with AD. Histologically, aged AGMs displayed pathological hallmarks of the disease, plaques, and 2 AGMs showed evidence of neurofibrillary tangle-like structures. We hypothesized and confirmed that AGMs have age-related cognitive deficits via a prefrontal cortex-dependent cognition test, and that symptomatic treatments that improve cognition in AD patients show efficacy in AGMs. These data suggest that the AGM could represent a novel and improved translational model to assist in the development of therapeutics for AD.
虽然已经报道了许多阿尔茨海默病（AD）的临床前模型，但没有一种能完全再现该疾病。为了确定合适的临床前疾病模型，我们对 2 种高级物种（非洲绿猴和恒河猴）的年龄相关变化进行了特征描述。背外侧前额叶皮层和视觉皮层的基因表达谱显示，AGM 存在与 AD 明显相似的年龄相关性变化，而老年恒河猴与健康老年人最相似。从生物化学角度来看，AGM 脑脊液中 tau、磷酸化 tau 和淀粉样β的年龄相关性变化与 AD 一致。组织学上，老年 AGM 显示出疾病的病理特征，斑块，并且 2 只 AGM 显示出神经原纤维缠结样结构的证据。我们假设并通过前额叶皮层依赖的认知测试证实，AGM 存在与年龄相关的认知缺陷，并且改善 AD 患者认知的症状治疗在 AGM 中显示出疗效。这些数据表明，AGM 可能代表一种新型和改进的转化模型，有助于 AD 治疗药物的开发。
