期刊
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
卷 1794, 期 10, 页码 1537-1548出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbapap.2009.06.022
关键词
A beta 40; A beta 42; Calcium; Amyloid; Alzheimer's
资金
- Alzheimer's Disease Association [IIRG-04-1153]
- Kurt and Johanna Immerwahr Fund for Alzheimer Research
Alzheimer's disease (AD) in humans is a common progressive neurodegenerative disease, associated with cognitive dysfunction, memory loss and neuronal loss. Alzheimer peptides A beta 40 and A beta 42 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 A beta 42 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 A beta 42 changed from an unfolded to a predominantly P-sheet conformation. These concentrations of Ca2+ greatly decreased the lag time for A beta 42 fibril formation, measured with thioflavin T. However, the elongation rate was apparently unaffected. Ca2+ appears to predominantly accelerate the nucleation stage of A beta 42 on pathway to the Alzheimer's fibril formation. Unlike A beta 42, Ca2+ was not observed to trigger similar effect at any stage during the study of fibrillation kinetics of A beta 40 by any techniques. A beta 40 and A beta 42 seem to have distinct aggregation pathways. (C) 2009 Elsevier B.V. All rights reserved.
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