Okazawa Hitoshi
Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University.
Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(6):361-377. doi: 10.2183/pjab.93.022.
The concept of neurodegenerative diseases and the therapeutics targeting these intractable diseases are changing rapidly. Protein aggregation as the top of pathological cascade is now challenged, and many alternative ideas are proposed. Early molecular pathologies before microscopic detection of diseases protein aggregates, which I propose to call "Ultra-Early Phase pathologies or phase 0 pathologies", are the focus of research that might explain the failures of clinical trials with anti-Aβ antibodies against Alzheimer's disease. In this review article, I summarize the critical issues that should be successfully and consistently answered by a new concept of neurodegeneration. For reevaluating old concepts and reconstructing a new concept of neurodegeneration that will replace the old ones, non-biased comprehensive approaches including proteome combined with systems biology analyses will be a powerful tool. I introduce our recent efforts in this orientation that have reached to the stage of non-clinical proof of concept applicable to clinical trials.
神经退行性疾病的概念以及针对这些难治性疾病的治疗方法正在迅速变化。作为病理级联顶端的蛋白质聚集现正受到挑战，并且提出了许多其他观点。在显微镜检测到疾病蛋白质聚集体之前的早期分子病理学，我提议将其称为“超早期病理学或0期病理学”，是可能解释针对阿尔茨海默病的抗Aβ抗体临床试验失败原因的研究重点。在这篇综述文章中，我总结了神经退行性变的新概念应成功且一致回答的关键问题。为了重新评估旧概念并构建一个将取代旧概念的神经退行性变新概念，包括蛋白质组学与系统生物学分析相结合的无偏综合方法将是一个强大的工具。我介绍了我们在这个方向上最近所做的努力，这些努力已达到适用于临床试验的非临床概念验证阶段。
