JBC study shows that bigger isn't necessarily better for amyloid proteins


Bethesda, MD Scientists at the University of California, Irvine have found evidence that disputes the popular belief that the long, insoluble amyloid fibrils found in amyloid-related diseases are what causes neurotoxicity. By comparing amyloid protein aggregates of different lengths, the researchers have shown that it is actually the smaller, soluble, oligomeric form of the proteins that interfere with cellular functioning.

The research appears as the "Paper of the Week" in the April 29 issue of the Journal of Biological Chemistry (JBC), an American Society for Biochemistry and Molecular Biology journal.

There are more than 100 human amyloid-related diseases, all caused by normally soluble proteins that have misfolded and aggregated. These diseases include Alzheimer's, Huntington's, Parkinson's and prion diseases. When the proteins that cause these diseases misfold, the singular proteins (monomers) form small soluble protein clusters called oligomers. As more proteins bind to the oligomers, they change shape, grow longer, and eventually become insoluble fibrils.

Originally, it was thought that the fibrils caused the neurotoxicity associated with these diseases. "Plaques and fibrils are invariably associated with the diseases, but this does not establish causality," notes study author Dr. Charles G. Glabe of the University of California Irvine. "The conundrum is that for many of these diseases, there are individuals who have large amounts of plaques or fibrillar aggregates but are without disease symptoms."

In order to explain this phenomenon, researchers hypothesize that the small oligomers that are intermediates in fibril formation, rather than the large fibrillar aggregates, are the culprits in neurotoxicity. Now, in their JBC paper, Dr. Glabe and his colleagues provide evidence to implicate these soluble intermediates and to explain just how the oligomers exert their effects on cells.

The researchers made preparations of 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.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.