ABETA FIBRILS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默病（AD）的病理标志是聚集的淀粉样β肽（A？）大脑中的老年斑 A？1-42，在老年斑中发现的主要肽，具有自聚集成？折叠片构象以形成纤维状淀粉样蛋白（fA？）。致密的老年斑由fA？的致密聚集体组成;这种积累被广泛认为是AD发病机理中的基本事件，引发了一连串的有害过程，包括氧化应激、炎症和神经毒性的诱导。 过去十年的研究表明，多酚是在各种“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，似乎在预防各种疾病方面发挥作用。 几个小组最近发现，一些多酚能够抑制合成A？转化成纤维和低聚物。 研究得最好的是姜黄素，一种用于咖喱的香料（印度AD的发病率是美国的一半），抑制了A？如通过噻托溴铵-T（ThT）荧光和透射电子显微镜（TEM）检测的。 此外，AD小鼠模型（Tg 2576小鼠）从17至22个月的年龄喂养姜黄素有减少淀粉样蛋白斑块负荷相比，未经处理的小鼠，这表明对斑块发病机制的影响。许多其他多酚（包括单宁酸、杨梅素、桑色素、阿魏酸等）也已显示出体外抗淀粉样蛋白生成活性。虽然主要的焦点一直在抑制A？聚集，初步但间接的证据表明，多酚类物质可以促进体外淀粉样纤维解聚。 聚集和解聚的抑制之间的这种区别是重要的，因为其对疾病停滞与逆转的影响。 我们建议使用冷冻电子显微镜（cryo-EM），以确定姜黄素的影响后的淀粉样纤维的结构。

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.