Institute of Pharmacology and Toxicology, University of Zurich, Zurich, CH-8057, Switzerland.
Acta Neuropathol Commun. 2013 Sep 23;1:62. doi: 10.1186/2051-5960-1-62.
For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that APP and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic.
在过去的 20 年里，“淀粉样蛋白级联假说”一直主导着旨在理解、预防和治疗阿尔茨海默病（AD）的研究。在此期间，研究人员已经获得了大量的数据，并通过针对清除淀粉样蛋白沉积的治疗方法，在动物模型系统中成功治愈该疾病超过 300 次。然而，迄今为止，类似的策略在人类 AD 患者中并未取得成功。因此，在急于用旨在降低越来越年轻人群中β淀粉样蛋白（Aβ）水平的化合物进行进一步临床试验之前，重新评估最初的假设即大脑中 Aβ的积累是驱动 AD 的主要病理事件，这将是当务之急。在这里，我们通过强调支持替代假说的实验证据来质疑这一假设，该假说表明 APP 和 Aβ 是神经元应激/损伤系统的一部分，该系统被上调以对抗炎症/氧化应激相关的神经退行性变，这些退行性变可能由脑损伤、慢性感染或全身性疾病引发。在 AD 中，这种保护程序可能被遗传和其他风险因素所超越，或者在衰老过程中其维持可能变得失调。在这里，我们提供了一个假设性的例子，即汽车事故和安全气囊释放之间存在假设驱动的相关性，这与淀粉样蛋白焦点的演变类似，也为 AD 领域未能将与淀粉样蛋白相关的治疗策略在实验模型中的成功转化为临床应用提供了潜在解释。
