Models of membrane-bound Alzheimer's Abeta peptide assemblies

Authors

  • Yinon Shafrir,

    1. Laboratory of Cell Biology, Bldg. 37 Rm 2108, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4258
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  • Stewart Durell,

    1. Laboratory of Cell Biology, Bldg. 37 Rm 2108, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4258
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  • Nelson Arispe,

    1. Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, Bethesda, Maryland 20814
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  • H. Robert Guy

    Corresponding author
    1. Laboratory of Cell Biology, Bldg. 37 Rm 2108, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4258
    • 6510 Tahawash St., Cochiti Lake, NM 87083
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  • This article is a US government work and, as such, is in the public domain in the United States of America.

Abstract

Although it is clear that amyloid beta (Aβ) peptides play a pivotal role in the development of Alzheimer's disease, the precise molecular model of action remains unclear. Aβ peptide forms assemble both in aqueous solution and in lipid membranes. It has been proposed that deleterious effects occur when the peptides interact with membranes, possibly by forming Ca2+ permeant ion channels. In the accompanying manuscript, we propose models in which the C-terminus third of six Aβ42 peptides forms a six-stranded β-barrel in highly toxic soluble oligomers. Here we extend this hypothesis to membrane-bound assemblies. In these Aβ models, the hydrophobic β-barrel of a hexamer may either reside on the surface of the bilayer, or span the bilayer. Transmembrane pores are proposed to form between several hexamers. Once the β-barrels of six hexamers have spanned the bilayer, they may merge to form a more stable 36-stranded β-barrel. We favor models in which parallel β-barrels formed by N-terminus segments comprise the lining of the pores. These types of models explain why the channels are selective for cations and how metal ions, such as Zn2+, synthetic peptides that contain histidines, and some small organic cations may block channels or inhibit formation of channels. Our models were developed to be consistent with microscopy studies of Aβ assemblies in membranes, one of which is presented here for the first time. Proteins 2010. © 2010 Wiley-Liss, Inc.

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