Effects of zinc and carnosine on aggregation kinetics of Amyloid-β40 peptide

The accumulation and amyloid formation of amyloid-β (Aβ) peptides is closely associated with the pathology of Alzheimer's disease. The physiological environment wherein Aβ aggregation happens is crowded with a large variety of metal ions including Zn(2+). In this study, we investigated the role of Zn(2+) in regulating the aggregation kinetics of Aβ40 peptide. Our results show that Zn(2+) can shift a typical single sigmoidal aggregation kinetics of Aβ40 to a biphasic aggregation process. Zn(2+) aids in initiating the rapid self-assembly of monomers to form oligomeric intermediates, which further grow into amyloid fibrils in the first aggregation phase. The presence of Zn(2+) also retards the appearance of the second aggregation phase in a concentration dependent manner. In addition, our results show that a natural dipeptide, carnosine, can greatly alleviate the effect of Zn(2+) on Aβ aggregation kinetics, most likely by coordinating with the metal ion to form chelates. These results suggest a potential in vivo protective effect of carnosine against the cytotoxicity of Aβ by suppressing Zn(2+)-induced rapid formation of Aβ oligomers.