Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA.
Department of Chemistry, University of Illinois At Chicago, Chicago, IL, 60607, USA.
Sci Rep. 2021 Jan 8;11(1):247. doi: 10.1038/s41598-020-80042-5.
Alzheimer's disease is characterized by neuritic plaques, the main protein components of which are β-amyloid (Aβ) peptides deposited as β-sheet-rich amyloid fibrils. Cerebral Amyloid Angiopathy (CAA) consists of cerebrovascular deposits of Aβ peptides; it usually accompanies Alzheimer's disease, though it sometimes occurs in the absence of neuritic plaques, as AD also occurs without accompanying CAA. Although neuritic plaques and vascular deposits have similar protein compositions, one of the characteristic features of amyloids is polymorphism, i.e., the ability of a single pure peptide to adopt multiple conformations in fibrils, depending on fibrillization conditions. For this reason, we asked whether the Aβ fibrils in neuritic plaques differed structurally from those in cerebral blood vessels. To address this question, we used seeding techniques, starting with amyloid-enriched material from either brain parenchyma or cerebral blood vessels (using meninges as the source). These amyloid-enriched preparations were then added to fresh, disaggregated solutions of Aβ to make replicate fibrils, as described elsewhere. Such fibrils were then studied by solid-state NMR, fiber X-ray diffraction, and other biophysical techniques. We observed chemical shift differences between parenchymal vs. vascular-seeded replicate fibrils in select sites (in particular, Ala2, Phe4, Val12, and Gln15 side chains) in two-dimensional C-C correlation solid-state NMR spectra, strongly indicating structural differences at these sites. X-ray diffraction studies also indicated that vascular-seeded fibrils displayed greater order than parenchyma-seeded fibrils in the "side-chain dimension" (~ 10 Å reflection), though the "hydrogen-bond dimensions" (~ 5 Å reflection) were alike. These results indicate that the different nucleation conditions at two sites in the brain, parenchyma and blood vessels, affect the fibril products that get formed at each site, possibly leading to distinct pathophysiological outcomes.
阿尔茨海默病的特征是神经突斑块，其主要蛋白质成分是β-淀粉样蛋白（Aβ）肽，沉积为富含β-折叠的淀粉样纤维。脑淀粉样血管病（CAA）由 Aβ 肽在脑血管中的沉积组成；它通常伴随阿尔茨海默病发生，尽管有时在没有神经突斑块的情况下发生，就像 AD 也发生在没有伴随 CAA 的情况下一样。尽管神经突斑块和血管沉积物具有相似的蛋白质组成，但淀粉样蛋白的一个特征是多态性，即单一纯肽在纤维中采用多种构象的能力，这取决于纤维形成条件。出于这个原因，我们想知道神经突斑块中的 Aβ 纤维是否在结构上与脑血管中的纤维不同。为了解决这个问题，我们使用了接种技术，从脑实质或脑血管中的富含淀粉样蛋白的物质（以脑膜作为来源）开始。然后，将这些富含淀粉样蛋白的制剂添加到新鲜的、分散的 Aβ溶液中，以按照其他地方描述的方法生成复制纤维。然后通过固态 NMR、纤维 X 射线衍射和其他生物物理技术研究这些纤维。我们在二维 C-C 相关固态 NMR 光谱中观察到选择部位（特别是 Ala2、Phe4、Val12 和 Gln15 侧链）中实质与血管接种的复制纤维之间的化学位移差异，这强烈表明这些部位的结构差异。X 射线衍射研究还表明，血管接种的纤维在“侧链维度”（10Å 反射）显示出比实质接种的纤维更大的有序性，尽管“氢键维度”（5Å 反射）相似。这些结果表明，脑内两个部位（实质和血管）的不同成核条件影响在每个部位形成的纤维产物，可能导致不同的病理生理结果。
