Science Editor

When it folds wrongly, prion protein is a well-known culprit in a group of neurodegenerative diseases: the spongiform encephalitises, of which Creutzfeldt-Jacob disease and mad cow disease are the best-known - and most-feared - examples.

Now, a new study in the Feb. 26, 2009, issue of Nature suggests that normal prion protein may be involved in another neurodegenerative disease: Alzheimer's.

The work sheds light on both the function of normal prion protein, and on Amyloid-beta oligomers, precursors to the plaques that are the anatomical hallmark of Alzheimer's.

Those plaques were once thought to be not just a marker of the Alzheimer's, but its main problem as well. But recently, evidence has been accumulating that while the plaques themselves are not exactly harmless, their precursors - Amyloid-beta oligomers that results when secretases cut amyloid precursor protein - may be more toxic than the plaques themselves.

The results published in Nature "furthers the idea" that oligomers are toxic, senior author Stephen Strittmatter, professor of neurology and of neurobiology at Yale University School of Medicine, told BioWorld Today, and provide a possible mechanism. The toxicity of A-beta oligomers, he said, "has been, to some degree, a black box."

Strittmatter and his colleagues hypothesized that oligomers must have a binding partner, given that its toxic effects occur at nanomolar concentrations. They searched for such binding partners by linking oligomers to biotin and testing it for interaction with 225,000 proteins from mouse brains. They found that the oligomers bind tightly to prion protein.

The researchers next tested whether the interaction between oligomers and prion protein had any effect on long-term potentiation, the cellular mechanism by which memories are stored in the brain. During in vitro experiments, they showed that oligomers can impair long-term potentiation in brain slices from normal animals, but have no effect on long-term potentiation in brain slices from prion protein knockouts. Such knockouts showed normal long-term potentiation, suggesting that it is the interaction between oligomers and prion protein that interferes with long-term potentiation.

By pinpointing the interaction between A-beta oligomers and prion protein, the findings "identify prion protein as a potential target for Alzheimer's disease," Strittmatter said.

Current efforts attempt to "reduce the level [of Amyloid-beta], rather than to change how it works," mainly by targeting secretases. But secretases have multiple substrates, and some problems with toxicity have cropped up.

In contrast, blocking the interaction between prion protein and oligomers "may be more specific." And knockouts suggest that targeting prion protein is unlikely to lead to major side effects. "Prion protein is a protein you can get rid of completely, and rodents, at least, are healthy and happy."

Of course, whether something has an effect depends to some degree on how closely you look. While Strittmatter said that prion protein knockouts are "not grossly demented," he and his team currently are testing whether manipulating prion protein or its interaction with oligomers has more subtle effects, as the in vitro experiments on long-term potentiation suggest they might. "That's not really drug discovery per se," he said. "But it is further validation."

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