The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.
The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.
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DOI：
10.1371/journal.pone.0009505
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发表时间：
2010-03-03
期刊：
影响因子：
3.7
通讯作者：
Moir RD
中科院分区：
文献类型：
--
作者：
Soscia SJ;Kirby JE;Washicosky KJ;Tucker SM;Ingelsson M;Hyman B;Burton MA;Goldstein LE;Duong S;Tanzi RE;Moir RD
淀粉样蛋白(Aβ-Protein，Aβ)被认为是阿尔茨海默病(AD)病理的关键介质。β最常见的特征是一种附带的分解代谢副产物，缺乏正常的生理作用。然而，β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，对各种环境应激源做出调节，并能够诱导促炎活性。在这里，我们提供的数据支持Aβ作为抗菌肽(AMP)的体内功能。实验使用建立的体外试验来比较Aβ和LL-37的抗菌活性，LL-37是典型的人类AMP。研究结果表明，Aβ对8种常见和临床相关的微生物具有抗菌活性，效力相当于甚至在某些情况下高于LL-37。此外，我们发现AD全脑匀浆的抗菌活性显著高于年龄匹配的非AD样本，并且AMP的作用与组织Aβ水平相关。与Aβ介导的活性一致，增强的抗菌作用可通过用抗Aβ抗体清除AD脑组织匀浆的免疫耗竭而消失。我们的发现表明，β是一种迄今未被识别的AMP，可能在先天免疫系统中正常发挥作用。这一发现与目前Aβ介导的病理模型形成鲜明对比，并对正在进行的和未来的AD治疗策略具有重要意义。
The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ 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. Here, we provide data supporting an in vivo function for Aβ as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Aβ and LL-37, an archetypical human AMP. Findings reveal that Aβ 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 Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies.
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