five disease-related amyloid proteins, including amyloid beta- and prion peptides, in monomeric, oligomeric, and fibrillar forms and examined their effects on cells. They found that the oligomeric forms of the proteins, and not the monomeric or fibrillar forms, elevated intracellular calcium levels. The oligomers also caused rapid cellular leakage of fluorescent dyes, suggesting that these molecules cause a generalized increase in membrane permeability.

"Membrane impermeability is fundamental to life," explains Dr. Glabe. "Cells are unable to maintain a membrane potential if their membranes leak. This is a problem for neurons that use membrane potential for signaling across synapses. Oligomers don't have to kill the cells to cause problems for neurons."

Just how the oligomers cause the cells to leak remains to be determined. However, Dr. Glabe has his hypotheses. "The simplest explanation for why oligomers are specifically toxic is that the edges of beta sheets are toxic by causing membrane permeabilization. The native structures and the misfolded monomers are not toxic because there are no sheet edges. Fibrils are much less toxic because the sheet edges are only exposed at the two ends of a very long fibril."

Based on the above findings, Dr. Glabe and his colleagues have developed antibodies that may one day be used to treat or diagnose amyloid diseases. "We have discovered antibodies that specifically recognize the generic oligomer conformation and these antibodies block the toxicity of oligomers in vitro. This suggests that vaccination against amyloid oligomers may be a viable therapeutic approach that avoids inflammatory side effects because the oligomeric conformation is strictly pathological and non-native. The antibodies can also be used as a diagnostic tool to measure the amount of oligomers in the presence of a vast excess of native protein and fibrillar deposits," concludes Dr. Glabe.

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Contact: Nicole Kresge
nkresge@asbmb.org
301-634-7415
American Society for Biochemistry and Molecular Biology
14-Apr-2005

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