Salk Institute for Biological Studies, La Jolla, CA.
Yale J Biol Med. 2020 Jun 29;93(2):365-373. eCollection 2020 Jun.
Alzheimer's disease (AD) is the most common form of dementia with the numbers expected to increase dramatically as our society ages. There are no treatments to cure, prevent, or slow down the progression of the disease. Age is the single greatest risk factor for AD. However, to date, AD drug discovery efforts have generally not taken this fact into consideration. Multiple changes associated with brain aging, including neuroinflammation and oxidative stress, are important contributors to disease development and progression. Thus, due to the multifactorial nature of AD, the one target strategy to fight the disease needs to be replaced by a more general approach using pleiotropic compounds to deal with the complexity of the disease. In this perspectives piece, our alternative approach to AD drug development based on the biology of aging is described. Starting with plants or plant-derived natural products, we have used a battery of cell-based screening assays that reflect multiple, age-associated toxicity pathways to identify compounds that can target the aspects of aging that contribute to AD pathology. We have found that this combination of assays provides a replicable, cost- and time-effective screening approach that has to date yielded one compound in clinical trials for AD (NCT03838185) and several others that show significant promise.
阿尔茨海默病（AD）是最常见的痴呆症形式，随着社会老龄化，预计其发病率将大幅上升。目前尚无治愈、预防或减缓疾病进展的方法。年龄是 AD 的单一最大风险因素。然而，迄今为止，AD 药物研发工作通常没有考虑到这一事实。与大脑衰老相关的多种变化，包括神经炎症和氧化应激，是导致疾病发展和进展的重要因素。因此，由于 AD 的多因素性质，需要用更通用的方法来替代针对单一靶点的策略，使用多效化合物来应对疾病的复杂性。在这篇观点文章中，我们描述了一种基于衰老生物学的 AD 药物开发的替代方法。从植物或植物源性天然产物开始，我们使用了一系列基于细胞的筛选检测方法，这些方法反映了多种与年龄相关的毒性途径，以鉴定能够针对导致 AD 病理的衰老方面的化合物。我们发现，这种组合检测方法提供了一种可复制、具有成本效益和时间效益的筛选方法，迄今为止，已有一种用于 AD 的临床试验化合物（NCT03838185）和其他几种显示出显著前景的化合物。
