Ca(2+), within the physiological concentrations, selectively accelerates Abeta42 fibril formation and not Abeta40 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 Abeta40 and Abeta42 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 Ca(2+) ions at physiological concentrations greatly accelerate the rate of aggregation of Abeta42 to form intermediate soluble associated species and fibrils. In the presence of 1 or 2 mM Ca(2+), CD spectra indicated that the secondary structure of Abeta42 changed from an unfolded to a predominantly beta-sheet conformation. These concentrations of Ca(2+) greatly decreased the lag time for Abeta42 fibril formation, measured with thioflavin T. However, the elongation rate was apparently unaffected. Ca(2+) appears to predominantly accelerate the nucleation stage of Abeta42 on pathway to the Alzheimer's fibril formation. Unlike Abeta42, Ca(2+) was not observed to trigger similar effect at any stage during the study of fibrillation kinetics of Abeta40 by any techniques. Abeta40 and Abeta42 seem to have distinct aggregation pathways.
Ahmad
Atta
A
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ahmadatt@umich.edu
Muzaffar
Mahvish
M
Ingram
Vernon M
VM
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology*; D002942:Circular Dichroism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000096:biosynthesis / Q000737:chemistry; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D020836:Protein Structure, Quaternary / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D012995:Solubility
D000682:Amyloid; D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002118:Calcium