Laboratory of Neurochemistry & Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium.
Br J Pharmacol. 2011 Oct;164(4):1285-300. doi: 10.1111/j.1476-5381.2011.01299.x.
With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease-modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease-modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease-related research as valid models enable the appraisal of early pathological processes - which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence-accelerated mice, chemical and lesion-induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions.
随着基于生物标志物分析预测轻度认知障碍向痴呆转化的可行性不断提高，对有效疾病修饰化合物的迫切需求变得更加关键。尽管进行了密集的研究，但针对有目的的靶点发现，其潜在的病理生理机制仍未得到充分记录。基于有效动物模型的转化研究可能有助于缓解当前阿尔茨海默病药物市场中一些未满足的需求，包括疾病修饰、提高疗效和安全性、减少治疗无反应患者的数量和提高患者依从性。在与阿尔茨海默病相关的研究中，动物模型的开发和表型分析确实至关重要，因为有效的模型能够评估早期的病理过程——这些过程在患者中往往无法获得，从而进行后续的靶点发现和评估。本文综述总结并批判性地评价了现有的动物模型，并讨论了它们对阿尔茨海默病药物发现管道的价值。涉及的模型包括各种物种的自发性模型，包括加速衰老的小鼠、化学和损伤诱导的啮齿动物模型，以及在果蝇、秀丽隐杆线虫、斑马鱼和啮齿动物中开发的基因修饰模型。尽管存在高度有效的动物模型，但目前没有任何一种模型能够重现人类阿尔茨海默病的所有方面，人们应该始终意识到从模式生物不恰当地推断到需要数十年才能发展且主要涉及更高认知功能的人类疾病的潜在危险。
