Glycation affects fibril formation of Aβ peptides

Abstract

Increasing evidence shows that β-amyloid (Aβ) 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 Aβ 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 Aβ40 and Aβ42 peptides, the aggregation pathway, and the morphologies of the resulting aggregates. We found that glycation significantly slows down but does not prevent β-conversion to mature fibers. We propose that the previously reported higher toxicity of the glycated Aβ peptides could be explained by a longer persistence in an oligomeric form, usually believed to be the toxic species.

Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease

“…Advanced glycation end products (AGEs) are stable end products of a non-enzymatic post-translational glycation reaction [78,79]. In vivo, AGEs are mainly formed through the reaction of proteins with dicarbonyl compounds, such as methylglyoxal (MGO), a by-product of glycolysis [78].…”

“…As described above, glycated Aβ demonstrates greater toxicity than non-glycated Aβ [81]. To address the associated mechanisms, a recent study reacted Aβ 40 or Aβ 42 with MGO in vitro and then analyzed the formation of aggregates and fibers and its kinetics using the thioflavin T assay and atomic force microscopy [79]. The authors found that MGO-induced glycation reduced the aggregation speed of Aβ 40 and Aβ 42 .…”

“…Consequently, formation of mature fibers was slowed down. This would suggest the accumulation of Aβ oligomers because the slower fiber formation process could reflect a stabilizing effect on the oligomeric state [79]. Importantly, intermediate aggregates of Aβ, such as oligomers, are particularly cytotoxic and closely implicated in AD pathogenesis [7,8,79,82].…”

“…This would suggest the accumulation of Aβ oligomers because the slower fiber formation process could reflect a stabilizing effect on the oligomeric state [79]. Importantly, intermediate aggregates of Aβ, such as oligomers, are particularly cytotoxic and closely implicated in AD pathogenesis [7,8,79,82]. Thus, Aβ glycation could result in the extended presence of the toxic oligomeric form, thereby leading to higher toxicity compared to non-glycated Aβ [79].…”

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

“…APP cleaved by γ-secretase occurs within the transmembrane region, producing different Aβ variants. Among these fragments, Aβ40 is the main product and Aβ42 is the most toxic product [70].…”