Ca2+, within the physiological concentrations, selectively accelerates Aβ42 fibril formation and not Aβ40 in vitro

Alzheimer's disease (AD) in humans is a common progressive neurodegenerative disease, associated with cognitive dysfunction, memory loss and neuronal loss. Alzheimer peptides Aβ40 and Aβ42 are precursors of the amyloid fibers that accumulate in the brain of patients. These peptides misfold and the monomers aggregate to neurotoxic oligomers and fibrils. Thus, the aggregation kinetics of these peptides is central to understanding the etiology of AD. Using size exclusion chromatography as well as filtration methods, we report here that Ca2+ ions at physiological concentrations greatly accelerate the rate of aggregation of Aβ42 to form intermediate soluble associated species and fibrils. In the presence of 1 or 2 mM Ca2+, CD spectra indicated that the secondary structure of Aβ42 changed from an unfolded to a predominantly β-sheet conformation. These concentrations of Ca2+ greatly decreased the lag time for Aβ42 fibril formation, measured with thioflavin T. However, the elongation rate was apparently unaffected. Ca2+ appears to predominantly accelerate the nucleation stage of Aβ42 on pathway to the Alzheimer's fibril formation. Unlike Aβ42, Ca2+ was not observed to trigger similar effect at any stage during the study of fibrillation kinetics of Aβ40 by any techniques. Aβ40 and Aβ42 seem to have distinct aggregation pathways.