Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
PLoS One. 2010 Mar 3;5(3):e9505. doi: 10.1371/journal.pone.0009505.
The amyloid beta-protein (Abeta) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Abeta is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Abeta has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities.
METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide data supporting an in vivo function for Abeta as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Abeta and LL-37, an archetypical human AMP. Findings reveal that Abeta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Abeta levels. Consistent with Abeta-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Abeta antibodies.
CONCLUSIONS/SIGNIFICANCE: Our findings suggest Abeta is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Abeta-mediated pathology and has important implications for ongoing and future AD treatment strategies.
淀粉样β-蛋白（Abeta）被认为是阿尔茨海默病（AD）病理的关键介质。Abeta 通常被认为是一种偶然的分解代谢副产物，缺乏正常的生理作用。然而，Abeta 已被证明是许多不同受体和其他分子的特异性配体，通过复杂的运输途径运输，响应各种环境应激源进行调节，并能够诱导促炎活性。
方法/主要发现：在这里，我们提供了支持 Abeta 作为抗菌肽（AMP）具有体内功能的证据。实验使用已建立的体外测定法比较了 Abeta 和 LL-37（一种典型的人类 AMP）的抗菌活性。研究结果表明，Abeta 对八种常见的临床相关微生物具有抗菌活性，其效力与 LL-37 相当，在某些情况下甚至更强。此外，我们表明 AD 全脑匀浆的抗菌活性明显高于年龄匹配的非 AD 样本，并且 AMP 作用与组织 Abeta 水平相关。与 Abeta 介导的活性一致，用抗 Abeta 抗体免疫耗尽 AD 脑匀浆可消除增加的抗菌作用。
结论/意义：我们的研究结果表明，Abeta 是一种迄今为止尚未被识别的 AMP，它可能在固有免疫系统中正常发挥作用。这一发现与当前的 Abeta 介导的病理模型形成鲜明对比，并对正在进行和未来的 AD 治疗策略具有重要意义。
