Amyloid- metabolite sensing: biochemical linking of glycation modification and misfolding. Academic Article uri icon

abstract

  • 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- (A), 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 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 A42 and increase misfolding. Using mass spectrometry, modifications primarily occurred at the amino terminus. However, the metabolite methylglyoxal modified Arg5 in the A 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 and plaques by metabolic compounds. Thus, glycation potentially links metabolic dysfunction and A misfolding in AD, and may contribute to the AD pathogenesis. This association can further be expanded to raise the tantalizing concept that such A modification and misfolding can function as a sensor of metabolic dysfunction.

published proceedings

  • J Alzheimers Dis

author list (cited authors)

  • Fawver, J. N., Schall, H. E., Petrofes Chapa, R. D., Zhu, X., & Murray, I.

citation count

  • 22

complete list of authors

  • Fawver, Janelle N||Schall, Hayley E||Petrofes Chapa, Rachel D||Zhu, Xiongwei||Murray, Ian VJ

publication date

  • May 2012