Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
Department of Psychology, The Ohio State University, Columbus, OH, USA.
J Alzheimers Dis. 2018;62(4):1495-1506. doi: 10.3233/JAD-171133.
The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.
β淀粉样蛋白（Aβ）肽长期以来一直被认为是阿尔茨海默病（AD）的主要致病因素。然而，在临床试验中，成功减少大脑中的 Aβ 负担并没有减缓认知能力下降，在某些情况下，甚至导致了不良后果。虽然这些结果可以有不同的解释，但对 Aβ 的认识越来越深入，考虑到以下事实：该肽在进化上是保守的，并且在认知正常的个体一生中都存在。最近的证据表明，Aβ 作为一种抗菌肽（AMP）发挥作用，AMP 是一类先天免疫防御分子，利用纤维状结构来保护宿主免受各种病原体的侵害。在人类和动物模型中，大脑感染通常会导致淀粉样前体蛋白（AβPP）的淀粉样蛋白形成过程增加，从而产生 Aβ 的纤维状聚集物。来自体外和体内研究的证据表明，Aβ 寡聚物通过形成纤维状结构来捕获病原体并破坏细胞膜，具有强大的广谱抗菌特性。重要的是，Aβ 的过表达赋予了对细菌和病毒感染的更高抵抗力。Aβ 的抗菌作用可以解释为什么在一些减少 Aβ 的 AD 临床试验中观察到感染率增加的原因。也许一旦治疗策略开始考虑这种神秘肽的可能生理功能，AD 的治疗进展就会加速。
