Crawford F, Soto C, Suo Z, Fang C, Parker T, Sawar A, Frangione B, Mullan M
Roskamp Institute, University of South Florida, Tampa 33613, USA.
FEBS Lett. 1998 Oct 9;436(3):445-8. doi: 10.1016/s0014-5793(98)01170-3.
The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-1 induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity. To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis--Dutch type (A beta(22Q)(1-40)). The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40). However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure. The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta. This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them.
先前的研究表明，β-淀粉样蛋白（Aβ）肽在体外可增强去氧肾上腺素或内皮素-1诱导的主动脉环收缩。Aβ血管活性的特征（剂量、片段长度、作用时间）表明其机制不同于Aβ细胞毒性。为了确定Aβ的哪些特性决定其对血管的生物活性，我们单独或联合研究了多种Aβ类似物和片段，包括那些已知与阿尔茨海默病（Aβ(1-42)）和荷兰型遗传性淀粉样脑血管病（Aβ(22Q)(1-40)）相关的物质。血管活性似乎与肽在溶液中所采取的构象有关。富含β折叠片层的Aβ(1-42)和Aβ(22Q)(1-40)的血管活性均低于主要为无规卷曲的野生型Aβ(1-40)。然而，血管活性最强的Aβ肽是包含无规卷曲和β片层结构混合物的组合。含有低水平或高水平β折叠构象的肽比含有中等量这种结构基序的肽血管活性更低，这一发现使我们能够提出在无规卷曲和β折叠之间存在一种过渡形式，它是Aβ的血管活性形式。这是首次鉴定出Aβ构象中间体并确定与其相关的生物活性。
