Alzheimer's disease (AD) is characterized by the presence of extracellular senile plaques formed by β-amyloid (Aβ) peptides in the patient's brain. Previous studies have shown that the plaques in the AD brains are co-localized with the advanced glycation end products (AGEs), which is mainly formed from a series of non-enzymatic reactions of proteins with reducing sugars or reactive dicarbonyls. Moreover, AGEs were also demonstrated to increase the neurotoxicity of the Aβ peptides. In order to clarify the impact of glycation on Aβ aggregation, we synthesized two glycated Aβ42 peptides by replacing Lys16 and Lys28 with Nε-carboxymethyllysine respectively to mimic the occurrence of protein glycation. Afterwards, we monitored the aggregation kinetics and conformational change for two glycated peptides and compared with wild-type Aβ42. Furthermore, we also used fluorescence correlation spectroscopy to probe the early stage of peptide oligomerization and tested their abilities in copper binding and reactive oxygen species (ROS) production. Our data show that glycation significantly slows down the aggregation process but does not prevent the formation of mature fibrils. In addition, two glycated Aβ42 peptides maintain binding affinity with copper ion and the ability to produce ROS. We speculated that the higher toxicity of glycated Aβ42 which glycation occurs at position 28 might result from its relative stable oligomeric form. The data shown here emphasized the ways to prevent glycation or target glycated proteins in AD treatments.
|Effective start/end date||2018/08/01 → 2021/02/01|
- Alzheimer's disease; β-amyloid; advanced glycation end products (AGEs); reactive oxygen species (ROS); stable oligomer
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