title: Ca(2+) Interacts with Glu-22 of Aβ(1-42) and Phospholipid Bilayers to Accelerate the Aβ(1-42) Aggregation Below the Critical Micelle Concentration.
abstract: The amyloid cascade hypothesis links the amyloid-β (Aβ) peptide aggregation to neuronal cell damage and ultimately the etiology of Alzheimer's disease (AD). Although Aβ aggregation has been known to accelerate at cell membranes, the exact mechanism of Aβ 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 Ca(2+) ions, in conjunction with lipid bilayer, lower the threshold concentration for Aβ aggregation (>a few micromolar in vitro) to physiological levels (low nanomolar). Circular dichroism spectroscopy reveals that Ca(2+) ions and the lipid bilayer concertedly accelerate the conformational change or misfolding of Aβ peptides. Molecular dynamics calculation indicates that Ca(2+) is sandwiched between Glu-22 of Aβ and the lipid phosphate group. SPR experiments conducted using an E22G mutant confirmed the strong interaction among Ca(2+), Aβ(1-42), and the phospholipid bilayer. With the C- and N-termini of the Aβ dimer fully exposed for the attachment of additional Aβ molecules, fibrils formed with the Ca(2+)-anchored Aβ nuclei appear to interact with lipid bilayers differently from those preformed in solution. Thus, similar to the role of Ca(2+) in enriching islet amyloid polypeptides in the pancreas of diabetic patients ( Biophys. J. 2013 , 104 , 173 - 184 ) and the "Ca(2+) bridge" in mediating membrane interaction with α-synuclein in the Parkinson's disease ( Biochemistry , 2006 , 45 , 10947 - 10956 ), the influence of Ca(2+) on the Aβ adsorption at cell membranes, which leads to neuronal membrane damage in AD, cannot be overlooked.
authors.affiliation: Department of Chemistry and Biochemistry, California State University , Los Angeles, California 90032, United States.|College of Chemistry and Chemical Engineering, Central South University , Changsha, Hunan 410083, P. R. China.
authors.forename: Xinyao
authors.initials: X
authors.lastname: Yi
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University , Changsha, Hunan 410083, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, California State University , Los Angeles, California 90032, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Gong
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Chemistry and Biochemistry, California State University , Los Angeles, California 90032, United States.
authors.forename: Narek
authors.initials: N
authors.lastname: Darabedian
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Biochemistry, California State University , Los Angeles, California 90032, United States.
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008823:Micelles; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008823:Micelles; D010446:Peptide Fragments; D010743:Phospholipids; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D002118:Calcium