Division of Adult Psychiatry, Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
Division of Nuclear Medicine and Molecular Imaging, Diagnostic Department, Geneva University and Geneva University Hospitals, Geneva, Switzerland.
Curr Alzheimer Res. 2020;17(2):112-125. doi: 10.2174/1567205017666200304085513.
Alzheimer's Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.
阿尔茨海默病（AD）是最常见的神经退行性疾病和痴呆症的病因。AD 的病理学特征是淀粉样斑块和过度磷酸化 Tau 的神经原纤维缠结，在过去的一个世纪中，AD 病理学得到了深入研究。在一系列针对淀粉样蛋白或 Tau 沉积的药物试验失败后，目前，希望寄托在一项备受争议的 III 期试验和其他正在进行的试验的积极结果上。与此同时，一些方法针对神经炎症，AD 的另一个核心特征。治疗策略最初在动物模型中进行评估，各种药物在这些模型中显示出对目标的作用（减少淀粉样蛋白、Tau 和神经炎症），有时还能改善认知障碍。然而，重要的是要记住，啮齿动物模型的大脑比人类的大脑复杂程度低，而且病理通常没有得到充分的体现。尽管它们是药物发现过程中不可或缺的工具，但必须谨慎看待从动物模型中获得的结果。在这篇综述中，我们重点介绍了针对淀粉样蛋白、Tau 和神经炎症的疾病修饰疗法的现状，特别关注了动物模型中积极的临床前结果与临床试验失败之间的差异。
