Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Department of Pharmacology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Graduate Program in Biological Sciences: Biochemistry (PPGBioq), UFRGS, Porto Alegre, RS, Brazil; Pharmacology and Therapeutics (PPGFT), UFRGS, Porto Alegre, RS, Brazil; McGill Centre for Studies in Aging, McGill University, Montreal, Canada; Brain Institute of Rio Grande do Sul, PUCRS, Porto Alegre, Brazil.
Neurosci Biobehav Rev. 2023 Sep;152:105246. doi: 10.1016/j.neubiorev.2023.105246. Epub 2023 May 24.
Over the past decades, significant efforts have been made to understand the precise mechanisms underlying the pathogenesis of Alzheimer's disease (AD), the most common cause of dementia. However, clinical trials targeting AD pathological hallmarks have consistently failed. Refinement of AD conceptualization, modeling, and assessment is key to developing successful therapies. Here, we review critical findings and discuss emerging ideas to integrate molecular mechanisms and clinical approaches in AD. We further propose a refined workflow for animal studies incorporating multimodal biomarkers used in clinical studies - delineating critical paths for drug discovery and translation. Addressing unresolved questions with the proposed conceptual and experimental framework may accelerate the development of effective disease-modifying strategies for AD.
在过去的几十年中，人们做出了巨大的努力来理解阿尔茨海默病（AD）发病机制的精确机制，AD 是痴呆症最常见的原因。然而，针对 AD 病理标志物的临床试验一直失败。改进 AD 的概念化、建模和评估是开发成功疗法的关键。在这里，我们回顾了关键发现，并讨论了将 AD 分子机制和临床方法相结合的新观点。我们进一步提出了一个改进的动物研究工作流程，该流程结合了临床研究中使用的多模态生物标志物 - 为药物发现和转化描绘关键路径。通过所提出的概念和实验框架解决未解决的问题，可能会加速 AD 有效疾病修饰策略的开发。
