Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 607K) PPT slides of all figures Correction (v128,p755) Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JGP Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sokolov, Y. Articles by Hall, J. E. Search for Related Content PubMed PubMed Citation Articles by Sokolov, Y. Articles by Hall, J. E. Related Collections Related Article Social Bookmarking                      What's this?

¹ Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA 92697
² Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697
³ Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Correspondence to James E. Hall: jhall{at}uci.edu

The amyloid hypothesis of Alzheimer's toxicity has undergone a resurgence with increasing evidence that it is not amyloid fibrils but a smaller oligomeric species that produces the deleterious results. In this paper we address the mechanism of this toxicity. Only oligomers increase the conductance of lipid bilayers and patch-clamped mammalian cells, producing almost identical current–voltage curves in both preparations. Oligomers increase the conductance of the bare bilayer, the cation conductance induced by nonactin, and the anion conductance induced by tetraphenyl borate. Negative charge reduces the sensitivity of the membrane to amyloid, but cholesterol has little effect. In contrast, the area compressibility of the lipid has a very large effect. Membranes with a large area compressibility modulus are almost insensitive to amyloid oligomers, but membranes formed from soft, highly compressible lipids are highly susceptible to amyloid oligomer-induced conductance changes. Furthermore, membranes formed using the solvent decane (instead of squalane) are completely insensitive to the presence of oligomers. One simple explanation for these effects on bilayer conductance is that amyloid oligomers increase the area per molecule of the membrane-forming lipids, thus thinning the membrane, lowering the dielectric barrier, and increasing the conductance of any mechanism sensitive to the dielectric barrier.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

Amyloid Ion Channels: A Porous Argument or a Thin Excuse?

David Eliezer
J. Gen. Physiol. 2006 128: 631-633. [Full Text] [PDF]

This article has been cited by other articles:

				G. Valincius, F. Heinrich, R. Budvytyte, D. J. Vanderah, D. J. McGillivray, Y. Sokolov, J. E. Hall, and M. Losche Soluble Amyloid {beta}-Oligomers Affect Dielectric Membrane Properties by Bilayer Insertion and Domain Formation: Implications for Cell Toxicity Biophys. J., November 15, 2008; 95(10): 4845 - 4861. [Abstract] [Full Text] [PDF]

				M. O. W. Grimm, H. S. Grimm, I. Tomic, K. Beyreuther, T. Hartmann, and C. Bergmann Independent Inhibition of Alzheimer Disease {beta}- and {gamma}-Secretase Cleavage by Lowered Cholesterol Levels J. Biol. Chem., April 25, 2008; 283(17): 11302 - 11311. [Abstract] [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents