Cerebral amyloid angiopathy (CAA) is a vascular disorder that primarily involves deposition of the 40-residue–long β-amyloid peptide (Aβ40) in and along small blood vessels of the brain. CAA is often associated with Alzheimer's disease (AD), which is characterized by amyloid plaques in the brain parenchyma enriched in the Aβ42 peptide. Several recent studies have suggested a structural origin that underlies the differences between the vascular amyloid deposits in CAA and the parenchymal plaques in AD. We previously have found that amyloid fibrils in vascular amyloid contain antiparallel β-sheet, whereas previous studies by other researchers have reported parallel β-sheet in fibrils from parenchymal amyloid. Using X-ray fluorescence microscopy, here we found that copper strongly co-localizes with vascular amyloid in human sporadic CAA and familial Iowa-type CAA brains compared with control brain blood vessels lacking amyloid deposits. We show that binding of Cu(II) ions to antiparallel fibrils can block the conversion of these fibrils to the more stable parallel, in-register conformation and enhances their ability to serve as templates for seeded growth. These results provide an explanation for how thermodynamically less stable antiparallel fibrils may form amyloid in or on cerebral vessels by using Cu(II) as a structural cofactor.

中文翻译：

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铜可稳定淀粉样蛋白 β40 (Aβ40)-Iowa 变体的反向平行 β 片原纤维。


脑淀粉样血管病 (CAA) 是一种血管疾病，主要涉及 40 个残基长的 β-淀粉样肽 (Aβ40) 在大脑小血管内及其周围的沉积。 CAA 通常与阿尔茨海默病 (AD) 相关，其特征是脑实质中存在富含 Aβ42 肽的淀粉样斑块。最近的几项研究表明，CAA 中的血管淀粉样沉积物与 AD 中的实质斑块之间的差异背后存在结构起源。我们之前发现血管淀粉样蛋白中的淀粉样原纤维含有反平行β-折叠，而其他研究人员之前的研究报道了来自实质淀粉样蛋白的原纤维中的平行β-折叠。使用 X 射线荧光显微镜，我们发现，与缺乏淀粉样蛋白沉积的对照脑血管相比，铜与人类散发性 CAA 和家族性爱荷华型 CAA 大脑中的血管淀粉样蛋白强烈共定位。我们发现，Cu(II) 离子与反平行原纤维的结合可以阻止这些原纤维转化为更稳定的平行、对准构象，并增强它们作为种子生长模板的能力。这些结果解释了热力学稳定性较差的反平行原纤维如何通过使用 Cu(II) 作为结构辅助因子在脑血管内或脑血管上形成淀粉样蛋白。