Amyloid-β Metabolite Sensing: Biochemical Linking of Glycation Modification and Misfolding
Amyloid-β Metabolite Sensing: Biochemical Linking of Glycation Modification and Misfolding
复制标题
DOI：
10.3233/jad-2012-112114
复制
发表时间：
2012-01-01
影响因子：
4
通讯作者：
Murray, Ian V. J.
中科院分区：
文献类型：
--
作者：
Fawver, Janelle N.;Schall, Hayley E.;Murray, Ian V. J.
糖化是还原糖与蛋白质和脂质的反应，产生大量糖化产物、蛋白质修饰、交联和氧化应激。糖化反应在代谢功能障碍期间也会升高，例如阿尔茨海默病 (AD) 和唐氏综合症。这些反应增加了 tau 蛋白和淀粉样蛋白-β (Aβ) 等蛋白质的错误折叠，并与 AD 中的淀粉样斑块共定位。因此，糖化将代谢功能障碍与 AD 联系起来，并且可能在 AD 中起因果作用。我们已经表征了 Aβ 与代谢功能障碍期间升高的反应性代谢物的反应。一种代谢物甘油醛-3-磷酸是糖酵解的正常产物，而其他代谢物则与病理有关。我们的数据表明，脂质氧化产物丙二醛、羟基壬烯醛和糖化代谢物（甲基乙二醛、甘油醛和甘油醛-3-磷酸）会修饰 A beta(42) 并增加错误折叠。使用质谱分析，修饰主要发生在氨基末端。然而，代谢物甲基乙二醛修饰了 A beta 序列中的 Arg5。 4-羟基-2-壬烯醛修饰与我们之前的出版物类似。为了将这种修饰置于体内环境中，我们对 AD 脑组织进行了糖化终产物或晚期糖基化终产物 (AGE) 的染色。与之前的发现类似，AGE 与淀粉样斑块共定位。总之，我们证明了代谢化合物对 Aβ 和斑块的糖化作用。因此，糖化可能与 AD 中的代谢功能障碍和 Aβ 错误折叠有关，并可能导致 AD 发病机制。这种关联可以进一步扩展，以提出一个诱人的概念，即这种 Aβ 修饰和错误折叠可以作为代谢功能障碍的传感器。
Glycation is the reaction of a reducing sugar with proteins and lipids, resulting in myriads of glycation products, protein modifications, cross-linking, and oxidative stress. Glycation reactions are also elevated during metabolic dysfunction such as in Alzheimer's disease (AD) and Down's syndrome. These reactions increase the misfolding of the proteins such as tau and amyloid-beta (A beta), and colocalize with amyloid plaques in AD. Thus, glycation links metabolic dysfunction and AD and may have a causal role in AD. We have characterized the reaction of A beta with reactive metabolites that are elevated during metabolic dysfunction. One metabolite, glyceraldehyde-3-phosphate, is a normal product of glycolysis, while the others are associated with pathology. Our data demonstrates that lipid oxidation products malondialdehyde, hydroxynonenal, and glycation metabolites (methylglyoxal, glyceraldehyde, and glyceraldehyde-3-phosphate) modify A beta(42) and increase misfolding. Using mass spectrometry, modifications primarily occurred at the amino terminus. However, the metabolite methylglyoxal modified Arg5 in the A beta sequence. 4-Hydroxy-2-nonenal modifications were similar to our previous publication. To place such modifications into an in vivo context, we stained AD brain tissue for endproducts of glycation, or advanced glycation endproducts (AGE). Similar to previous findings, AGE colocalized with amyloid plaques. In summary, we demonstrate the glycation of A beta and plaques by metabolic compounds. Thus, glycation potentially links metabolic dysfunction and A beta misfolding in AD, and may contribute to AD pathogenesis. This association can further be expanded to raise the tantalizing concept that such A beta modification and misfolding can function as a sensor of metabolic dysfunction.