Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro.
Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro.
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DOI：
10.1038/srep29077
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发表时间：
2016-07-06
影响因子：
4.6
通讯作者：
Naiki H
中科院分区：
文献类型：
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作者：
Ozawa D;Nomura R;Mangione PP;Hasegawa K;Okoshi T;Porcari R;Bellotti V;Naiki H
c反应蛋白（CRP）和血清淀粉样蛋白P组分（SAP）是人类两种主要的经典戊烷素，它们是调节先天免疫系统的可溶性模式识别分子，但它们的伴侣活性尚不清楚。在这里，我们研究了它们对阿尔茨海默病淀粉样蛋白β (Aβ)（1-40）和与遗传性系统性淀粉样变性相关的D76N β2-微球蛋白（β2-m）淀粉样蛋白纤维形成的影响。CRP和SAP以剂量依赖性和亚化学计量学的方式以Ca2+不依赖的方式抑制a β(1-40)和D76N β2-m纤维的形成。CRP和SAP在原纤维形成途径上与新鲜和聚集的Aβ(1-40)和D76N β2-m相互作用。有趣的是，在Ca2+的存在下，SAP首先抑制，然后显著加速D76N β2-m纤维的形成。电镜下，D76N β2-m原纤维表面被五聚体SAP包裹。这些数据表明，SAP首先表现出抗淀粉样蛋白活性，可能是通过A面，其次是通过B面促淀粉样蛋白活性，提出了一个模型，SAP的促淀粉和抗淀粉样蛋白活性不是相互排斥的，而是反映了一个硬币的两面，即分别在B面和A面。最后，SAP抑制热诱导的人谷胱甘肽s -转移酶的无定形聚集。探讨了戊烷素在维持细胞外蛋白酶平衡中的可能作用。
C-reactive protein (CRP) and serum amyloid P component (SAP), two major classical pentraxins in humans, are soluble pattern recognition molecules that regulate the innate immune system, but their chaperone activities remain poorly understood. Here, we examined their effects on the amyloid fibril formation from Alzheimer’s amyloid β (Aβ) (1-40) and on that from D76N β2-microglobulin (β2-m) which is related to hereditary systemic amyloidosis. CRP and SAP dose-dependently and substoichiometrically inhibited both Aβ(1-40) and D76N β2-m fibril formation in a Ca2+-independent manner. CRP and SAP interacted with fresh and aggregated Aβ(1-40) and D76N β2-m on the fibril-forming pathway. Interestingly, in the presence of Ca2+, SAP first inhibited, then significantly accelerated D76N β2-m fibril formation. Electron microscopically, the surface of the D76N β2-m fibril was coated with pentameric SAP. These data suggest that SAP first exhibits anti-amyloidogenic activity possibly via A face, followed by pro-amyloidogenic activity via B face, proposing a model that the pro- and anti-amyloidogenic activities of SAP are not mutually exclusive, but reflect two sides of the same coin, i.e., the B and A faces, respectively. Finally, SAP inhibits the heat-induced amorphous aggregation of human glutathione S-transferase. A possible role of pentraxins to maintain extracellular proteostasis is discussed.