文摘
The amyloid cascade hypothesis links the amyloid-尾 (A尾) peptide aggregation to neuronal cell damage and ultimately the etiology of Alzheimer鈥檚 disease (AD). Although A尾 aggregation has been known to accelerate at cell membranes, the exact mechanism of A尾 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尾 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尾 peptides. Molecular dynamics calculation indicates that Ca2+ is sandwiched between Glu-22 of A尾 and the lipid phosphate group. SPR experiments conducted using an E22G mutant confirmed the strong interaction among Ca2+, A尾(1鈥?2), and the phospholipid bilayer. With the C- and N-termini of the A尾 dimer fully exposed for the attachment of additional A尾 molecules, fibrils formed with the Ca2+-anchored A尾 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.pan class="NLM_x">www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve"> pan>2013pan class="NLM_x">www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve">, pan>104pan class="NLM_x">www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve">, pan>173鈭?84) and the 鈥淐a2+ bridge鈥?in mediating membrane interaction with 伪-synuclein in the Parkinson鈥檚 disease ( Biochemistry,pan class="NLM_x">www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve"> pan>2006pan class="NLM_x">www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve">, pan>45pan class="NLM_x">www.w3.org/1998/Math/MathML" xmlns:ACS="http://namespace.acs.org/2008/acs" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:space="preserve">, pan>10947鈭?0956), the influence of Ca2+ on the A尾 adsorption at cell membranes, which leads to neuronal membrane damage in AD, cannot be overlooked.