Journal
BIOCHEMISTRY
Volume 54, Issue 41, Pages 6323-6332Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.5b00719
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Funding
- National Institutes of Health [R01-GM105898]
- National Key Basic Research Program of China [2014CB744502]
- Hunan Province of China
- National Science Foundation [1112105, CBET-0952624, CBET115844]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1112105] Funding Source: National Science Foundation
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [0952624] Funding Source: National Science Foundation
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The amyloid cascade hypothesis links the amyloid-beta (A beta) peptide aggregation to neuronal cell damage and ultimately the etiology of Alzheimer's disease (AD). Although A beta aggregation has been known to accelerate at cell membranes, the exact mechanism of A beta peptide deposition and the involvement of extracellular species are still largely unclear. Using surface plasmon resonance (SPR) and atomic force microscopy (AFM), we demonstrate that Ca2+ ions, in conjunction with lipid bilayer, lower the threshold concentration for A beta aggregation (>a few micromolar in vitro) to physiological levels (low nanomolar). Circular dichroism spectroscopy reveals that Ca2+ ions and the lipid bilayer concertedly accelerate the conformational change or misfolding of A beta peptides. Molecular dynamics calculation indicates that Ca2+ is sandwiched between Glu-22 of A beta and the lipid phosphate group. SPR experiments conducted using an E22G mutant confirmed the strong interaction among Ca2+, A beta(1-42), and the phospholipid bilayer. With the C- and N-termini of the A beta dimer fully exposed for the attachment of additional A beta molecules, fibrils formed with the Ca2+-anchored A beta nuclei appear to interact with lipid bilayers differently from those preformed in solution. Thus, similar to the role of Ca2+ in enriching islet amyloid polypeptides in the pancreas of diabetic patients (Biophys. J. 2013, 104, 173-184) and the Ca2+ bridge in mediating membrane interaction with alpha-synudein in the Parkinson's disease (Biochemistry, 2006, 45, 10947-10956), the influence of Ca2+ on the A beta adsorption at cell membranes, which leads to neuronal membrane damage in AD, cannot be overlooked.
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