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.

This paper propounds the Amyloids as Sensors and Protectors (ASAP) hypothesis. In this novel hypothesis, we provide evidence that amyloids are capable of sensing dysfunction, and after misfolding, initiate protective cellular responses. Amyloid proteins are initially protective, but chronic stress and overstimulation of the amyloid sensor leads to pathology. This proposed ASAP hypothesis has two sequential stages: (i) sensing, and then (ii) protection. Sensing involves a conformational change of amyloids in response to the cellular environment. The protection aspect translates conformational change into a cellular response via several mechanisms. The most obvious mechanism is that protein misfolding triggers the protective unfolded protein response, and thus downregulates protein translation and increases chaperone proteins. Other documented responses include metabolic pathways and microRNAs. This ASAP hypothesis has precedence, as amyloid sensors exist (evidenced by CPEB and Sup35), and both prion and amyloid-β sensing redox stress and metals. Our hypothesis expands on previous observations to link sensing with inciting protective cellular response. Furthermore, we substantiate the ASAP hypothesis with previously published evidence from several amyloid diseases. This novel hypothesis links disparate findings in amyloid diseases: metabolic dysfunction, unfolding protein response/chaperones, modification of amyloids, and nutrient or caloric sensing. While this hypothesis can be applied to Alzheimer's disease, it goes beyond the Alzheimer's context. Thus all amyloid proteins can potentially act as sensors of misfolding-causing stress. Finally, this hypothesis will allow for the sensor mechanism and metabolic dysfunction to serve as biomarkers of the diseases as well as therapeutic targets early in disease pathology.