Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA.
J Alzheimers Dis. 2012;30(1):63-73. doi: 10.3233/JAD-2012-112114.
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-β (Aβ), 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 Aβ 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 Aβ42 and increase misfolding. Using mass spectrometry, modifications primarily occurred at the amino terminus. However, the metabolite methylglyoxal modified Arg5 in the Aβ 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 Aβ and plaques by metabolic compounds. Thus, glycation potentially links metabolic dysfunction and Aβ misfolding in AD, and may contribute to the AD pathogenesis. This association can further be expanded to raise the tantalizing concept that such Aβ modification and misfolding can function as a sensor of metabolic dysfunction.
糖基化是还原糖与蛋白质和脂质的反应，导致无数糖基化产物、蛋白质修饰、交联和氧化应激。糖基化反应在代谢功能障碍如阿尔茨海默病 (AD) 和唐氏综合征中也会升高。这些反应增加了蛋白质如 tau 和淀粉样蛋白-β (Aβ) 的错误折叠，并与 AD 中的淀粉样斑块共定位。因此，糖基化将代谢功能障碍与 AD 联系起来，并可能在 AD 中起因果作用。我们已经描述了 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学有关。我们的数据表明，脂质氧化产物丙二醛、4-羟基壬烯醛和糖基化代谢物 (甲基乙二醛、甘油醛和甘油醛-3-磷酸) 修饰 Aβ42 并增加错误折叠。使用质谱法，修饰主要发生在氨基末端。然而，代谢物甲基乙二醛修饰了 Aβ 序列中的 Arg5。4-羟基-2-壬烯醛的修饰与我们之前的出版物相似。为了将这些修饰置于体内环境中，我们对 AD 脑组织中的糖基化终产物或晚期糖基化终产物 (AGE) 进行了染色。与之前的发现相似，AGE 与淀粉样斑块共定位。总之，我们证明了代谢化合物对 Aβ 和斑块的糖基化。因此，糖基化可能将代谢功能障碍与 AD 中的 Aβ 错误折叠联系起来，并可能有助于 AD 的发病机制。这种关联可以进一步扩展，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。
