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© The Rockefeller University Press, 0021-9525/2003/5/456-a $5.00
The Journal of Cell Biology, Volume 161, Number 3, 456-a-457

Shared amyloid oligomer structure proves toxic

Preincubation of the antibody with oligomers (open bars) protected cells, whereas absence of antibodies and control antibodies had no effect. Kayed/AAAS

It was previously thought that the toxicity of Aß and other amyloids resulted from large insoluble fibrils, but recently researchers have found that smaller soluble intermediates are cytotoxic. Now, Rakez Kayed, Elizabeth Head, Charles Glabe (University of California, Irvine, CA), and colleagues show that all of the soluble amyloid oligomers tested share a similar structure, and therefore also likely share a common mechanism of pathogenesis.

Numerous degenerative diseases show evidence of amyloid formation. When the Irvine team raised antibodies against soluble Aß oligomers, they obtained a highly specific antibody that binds to antigens based on structure, not amino acid sequence. The antibody binds to Aß oligomers, but not to Aß monomers or fibrils, or to the natively folded amyloid precursor protein. It also binds strongly and specifically to oligomers formed by numerous other amyloid proteins, including -synuclein, islet amyloid polypeptide, polyglutamine, human insulin, lysozyme, and prion peptide 106–126. Preincubation of the antibody with any of these oligomers blocks their cytotoxicity.

"One of the real canons of biochemistry is that structure determines function. So if they all have the same structure, then they must all have a similar function, and all be doing something similar that is bad," says Glabe. Yet, many of the proposed mechanisms make sense for only one of the numerous amyloid diseases, which rules them out in Glabe's view. The real twist, he says, is that about half of the proteins act extracellularly and half intracellularly, leaving pretty much only the plasma membrane as a shared target.

Reference:

Kayed, R., et al. 2003. Science. 300:486–489.[Abstract/Free Full Text]

Rabiya S. Tuma

rabiya{at}nasw.org

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This Article Full Text (PDF, 816K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tuma, R. S. Search for Related Content PubMed Articles by Tuma, R. S. Social Bookmarking                            What's this?