Abstract
Ascorbic acid (AsA) is an important antioxidant and enzyme cofactor in many biochemical processes. Most biological activities of AsA are closely related to its redox properties. Recent investigations have demonstrated that AsA is associated with amyloid-related diseases and can inhibit amyloid aggregation of polypeptides. In the present study, we determined the kinetics of AsA degradation and investigated the anti-amyloidogenic activities of AsA and its degradation products by utilizing insulin as a model polypeptide. The results showed that the half-life of AsA varied with the pH of the medium and the incubation temperature. The degradation products of AsA inhibited insulin fibrillation, with an activity positively correlated to the degree of AsA degradation. The degradation species, compared with intact AsA, also showed a stronger disruptive effect on mature amyloid fibrils and significantly decreased fibrillar cytotoxicity. Dehydroascorbic acid and diketogulonic acid, two key intermediates in AsA degradation, had similar anti-amyloidogenic activity toward the degradation species of AsA. The results of this work indicate that degradation of natural antioxidants must be considered when evaluating their anti-amyloidogenic effects. These insights into the action of AsA may also provide a novel route to understand its physiological/pharmacological roles in amyloid-related diseases.
Highlights
Amyloid fibrillation of protein molecules is associated with a variety of amyloid-related diseases, including Alzheimer’s disease, type 2 diabetes, and several systemic amyloidoses [1,2,3]
To determine the relationship between the degradation and anti-amyloidogenic activity of Ascorbic acid (AsA), we determined the instability of this molecule under the experimental conditions described above
diketogulonic acid (DKG) degraded rapidly and disappeared after 3 h of incubation (Figures S2 and S3). These results suggested that some degradation species of dehydroascorbic acid (DHA) and DKG were active in amyloid inhibition
Summary
Amyloid fibrillation of protein molecules is associated with a variety of amyloid-related diseases, including Alzheimer’s disease, type 2 diabetes, and several systemic amyloidoses [1,2,3]. Numerous studies have shown that under denaturing conditions, including acidic pH and high temperature, insulin molecules can assemble into amyloid fibrils with a variety of morphologies [8,9,10,11]. Because these fibrils have been well characterized using various methods, insulin is an ideal model system for studying amyloid aggregation and screening
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