ABETA FIBRILS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿尔茨海默病(AD)的一个病理特征是聚集的淀粉样β-多肽(A？)在大脑内的老年斑中。A？1-42是在老年斑中发现的主要多肽，具有显著的自我聚集成折叠片状构象以形成纤维淀粉样蛋白(FA？)的倾向。致密的老年斑由致密的FA？聚集组成；这种聚集被广泛认为是AD发病机制中的一个基本事件，启动了一系列有害的过程，包括诱导氧化应激、炎症和神经毒性。 过去十年的研究表明，多酚是一种天然物质，具有不同的酚类结构，存在于各种“健康食品”中，具有强大的抗氧化性能，似乎在预防各种疾病方面发挥了作用。几个研究小组最近发现，一些多酚能够抑制合成的A？在体外转化为纤维和低聚物。研究得最好的是姜黄素，它是咖喱中使用的肿瘤香料的有效成分(在印度AD的发病率是美国的)，能抑制A？用硫代黄素-T(THT)荧光和透射电子显微镜(TEM)检测。此外，17至22个月龄喂食姜黄素的AD小鼠模型(Tg2576小鼠)与未治疗的小鼠相比，淀粉样斑块负荷减少，这表明在斑块发病机制中有作用。许多其他多酚(包括单宁酸、杨梅素、桑色素、阿魏酸等)在体外也显示出抗淀粉样蛋白生成的活性。而主要的焦点一直放在抑制A？聚集，初步但间接的证据表明，多酚在体外可能促进淀粉样原纤维解聚。这种抑制聚集和解聚之间的区别是重要的，因为它意味着疾病的阻止和逆转。 我们建议使用冷冻电子显微镜(Cryo-EM)来确定受姜黄素影响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.