ABETA FIBRILS

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 阿尔茨海默氏病（AD）的一个病理特征是大脑内老年斑中聚集的淀粉样β肽（A？）的积累。 Aβ1-42是老年斑中发现的主要肽，具有明显的自我聚集倾向，形成β折叠片构象，从而形成纤维状淀粉样蛋白(fAβ)。致密的老年斑由致密的 fAβ 聚集体组成；人们普遍认为这种积累是 AD 发病机制中的一个基本事件，引发一系列有害过程，包括诱导氧化应激、炎症和神经毒性。 过去十年的研究表明，多酚是各种“健康食品”中发现的具有可变酚结构的天然物质，具有有效的抗氧化特性，并且似乎在预防多种疾病方面发挥着作用。 几个研究小组最近发现一些多酚能够抑制合成Aβ的聚集。在体外分解成原纤维和低聚物。 研究最深入的姜黄素是姜黄中的活性成分，姜黄是咖喱中使用的香料（印度 AD 的发病率与美国相当），它可以抑制 A？通过硫黄素-T (ThT) 荧光和透射电子显微镜 (TEM) 检测。 此外，与未治疗的小鼠相比，从 17 至 22 个月龄喂食姜黄素的 AD 小鼠模型（Tg2576 小鼠）淀粉样蛋白斑块负荷减少，表明姜黄素对斑块发病机制有影响。许多其他多酚（包括单宁酸、杨梅素、桑色素、阿魏酸等）也已被证明在体外具有抗淀粉样蛋白生成活性。虽然主要关注点是抑制 A?初步但间接的证据表明，多酚可能会促进淀粉样原纤维在体外的解聚。 聚集抑制和解聚之间的区别很重要，因为它对疾病停滞与逆转具有影响。 我们建议使用冷冻电子显微镜（cryo-EM）来确定姜黄素影响下的淀粉样原纤维的结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A pathological hallmark of Alzheimer's Disease (AD) is the accumulation of aggregated amyloid-beta peptides (A?) in senile plaques within the brain. A?1-42, the predominant peptide found in senile plaques, has a striking propensity to self-aggregate into a ?-pleated sheet conformation to form fibrillar amyloid (fA?). Compact senile plaques are comprised of dense aggregates of fA?; this accumulation is widely believed to be a fundamental event in the pathogenesis of AD, initiating a cascade of deleterious process including the induction of oxidative stress, inflammation, and neurotoxicity. Studies over the last decade have suggested that polyphenols, natural substances with variable phenolic structures found in various "health foods," possess potent antioxidant properties and appear to play a role in the prevention of a variety of diseases. Several groups have recently found that some polyphenols are capable of inhibiting the aggregation of synthetic A? into fibrils and oligomers in vitro. The best studied, curcumin, the active ingredient in tumerica spice used in curry (the incidence of AD in India is ¿ that in the US), inhibited the fibrilization of A? as detected by thioflavine-T (ThT) fluorescence, and transmission electron microscopy (TEM). Furthermore, an AD mouse model (Tg2576 mice) fed curcumin from 17 to 22 months of age had decreased amyloid plaque burden compared to untreated mice, suggesting an effect on plaque pathogenesis. A host of other polyphenols (including tannic acid, myricetin, morin, ferulic acid, amongst others) has also been shown to demonstrate anti-amyloidogenic activity in vitro. While the primary focus has been on the inhibition of A? aggregation, preliminary but indirect evidence suggests that polyphenols may promote amyloid fibril disaggregation in vitro. This distinction between the inhibition of aggregation and disaggregation is important because of its implications for disease arrest vs. reversal. We propose to use cryo-electron microscopy (cryo-EM) to determine the structure of the amyloid fibril upon the influence of curcumin.