Amyloid-β Metabolite Sensing: Biochemical Linking of Glycation Modification and Misfolding

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-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.

Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling

“…AGE-modification accelerates the aggregation of soluble Aβ proteins in vitro , and AGE adducts are enriched at least 3-fold in plaque samples from AD brains compared with age-matched controls [157, 158]. Brain enrichment of AGEs may impair neural cell function by promoting covalent cross-linking of cellular proteins, thereby impeding their normal activities, or alternatively by direct signalling through the receptor for AGE (RAGE) [159].…”

Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro

“…), in which AGEs may be related to formation of amyloid plaques (Fawver et al . ). Long‐term effects of fructose exposure were recently shown when maternal fructose exposure during gestation and lactation caused changes in forebrain mitochondria of male, aging offspring, affecting oxidative phosphorylation (Mortensen et al .…”

“…More recently, diabetic rats were found to have increased AGE levels in the brain (Aragno et al 2005). AGE formation in the brain increases with age and appears to be accelerated in brains of patients with Alzheimer's disease (Choei et al 2004;L€ uth et al 2005;Srikanth et al 2011), in which AGEs may be related to formation of amyloid plaques (Fawver et al 2012). Long-term effects of fructose exposure were recently shown when maternal fructose exposure during gestation and lactation caused changes in forebrain mitochondria of male, aging offspring, affecting oxidative phosphorylation (Mortensen et al 2014).…”

Glycation exacerbates the neuronal toxicity of β-amyloid

“…The long-live proteins are preferentially modified to form AGEs and the stability of A β makes it an ideal substrate for non-enzymatic glycation and formation of AGEs. Although in vitro studies show that A β can be glycated and the glycated A β contribute to the A β accumulation, 5, 6 it is currently not characterized whether A β is also glycated in vivo to form A β -AGEs and the role of A β -AGE in the pathogenesis of AD.…”