Glycation affects fibril formation of Aβ peptides

Increasing evidence shows that beta-amyloid (A beta) peptides, which are associated with Alzheimer disease (AD), are heavily glycated in patients, suggesting a role of this irreversible nonenzymatic post-translational modification in pathology. Previous reports have shown that glycation increases the toxicity of the A beta peptides, although little is known about the mechanism. Here, we used the natural metabolic by-product methylglyoxal as a glycating agent and exploited various spectroscopic methods and atomic force microscopy to study how glycation affects the structures of the A beta 40 and A beta 42 peptides, the aggregation pathway, and the morphologies of the resulting aggregates. We found that glycation significantly slows down but does not prevent beta-conversion to mature fibers. We propose that the previously reported higher toxicity of the glycated A beta peptides could be explained by a longer persistence in an oligomeric form, usually believed to be the toxic species.