%0 Journal Article
%T Synergistic Interactions between Alzheimer¡¯s A¦Â40 and A¦Â42 on the Surface of Primary Neurons Revealed by Single Molecule Microscopy
%A Chun-Chieh Chang
%A John Christian Althaus
%A Cynthia J. L. Carruthers
%A Michael A. Sutton
%A Duncan G. Steel
%A Ari Gafni
%J PLOS ONE
%D 2013
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0082139
%X Two amyloid-¦Â peptides (A¦Â40 and A¦Â42) feature prominently in the extracellular brain deposits associated with Alzheimer¡¯s disease. While A¦Â40 is the prevalent form in the cerebrospinal fluid, the fraction of A¦Â42 increases in the amyloid deposits over the course of disease development. The low in vivo concentration (pM-nM) and metastable nature of A¦Â oligomers have made identification of their size, composition, cellular binding sites and mechanism of action challenging and elusive. Furthermore, recent studies have suggested that synergistic effects between A¦Â40 and A¦Â42 alter both the formation and stability of various peptide oligomers as well as their cytotoxicity. These studies often utilized A¦Â oligomers that were prepared in solution and at ¦ÌM peptide concentrations. The current work was performed using physiological A¦Â concentrations and single-molecule microscopy to follow peptide binding and association on primary cultured neurons. When the cells were exposed to a 1:1 mixture of nM A¦Â40:A¦Â42, significantly larger membrane-bound oligomers developed compared to those formed from either peptide alone. Fluorescence resonance energy transfer experiments at the single molecule level reveal that these larger oligomers contained both A¦Â40 and A¦Â42, but that the growth of these oligomers was predominantly by addition of A¦Â42. Both pure peptides form very few oligomers larger than dimers, but either membrane bound A¦Â40/42 complex, or A¦Â40, bind A¦Â42 to form increasingly larger oligomers. These findings may explain how A¦Â42-dominant oligomers, suspected of being more cytotoxic, develop on the neuronal membrane under physiological conditions.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0082139