One such thesis concerns the identity of the toxic agent in Alzheimer's, Parkinson's, and other degenerative age-related diseases. For years, most researchers have backed the notion that clumps of long amyloid fibrils located in the brain and other organs are responsible for killing neurons and other cells in patients who have these conditions.

In Alzheimer's, these clumps are termed amyloid plaques and consist primarily of the polypeptide amyloid protein; in Parkinson's, they're called Lewy bodies and contain the protein -synuclein.

It has taken a while, but the hypothesis that a precursor of the insoluble amyloid fibril may be the more dangerous entity is now gaining ground. And some researchers further believe that the smaller, soluble precursor, which is often called an amyloid oligomer or protofibril, may do its damage by creating holes--pores or ion channels--in cellular membranes.

"The whole history of neurodegenerative disease has revolved around the observation of the fibrils," says Peter T. Lansbury Jr., an associate professor of neurology at Harvard Medical School. "People are fixated on them." Lansbury himself wasn't immune. "When I was at MIT, my whole lab was focused on the fibril," he concedes.

There's good reason for that fixation. "In all these neurodegenerative diseases, you get amyloid fibrils, and they all have very similar structures," Lansbury says. "You would think, 'Similar structure, similar function, and they're all involved in disease.' " But these high-visibility markers, which were first described in the 19th century, may prove to be red herrings.

In Lansbury's case, one of the first findings that weakened his commitment to the toxic-fibril theory was made by Christopher M. Dobson, professor of chemical and structural biology at the University of Cambridge, who showed that many proteins--including those that aren't associated with disease--"can form amyloid fibrils. And maybe an amyloid fibril is a default, stable structure. So maybe the fact that all these fibrils share a structure says more about the stability of that structure than it does about a shared function," Lansbury says.

"It may be that in the neurodegenerative diseases characterized by fibrillization--which is essentially all of them--the fibrillization produces, as an alternative product, an amyloid pore," Lansbury says. "We don't know whether the pore is formed on the pathway to the fibril or if there's a fork in the road somewhere and the protofibrils have a choice to either form a pore or form a fibril. We're trying to study that."

In 1993, Nelson J. Arispe, Eduardo Rojas, and Harvey B. Pollard of the Laboratory of Cell Biology & Genetics at the National Institutes of Health were the first to propose that, in addition to forming fibrils and plaques, amyloid protein might form ion channels in the membrane of neurons [Proc. Natl. Acad. Sci. USA, 90, 567 (1993)]. The channels could allow excess calcium and other cations to flow into the neurons, killing the cells and ultimately resulting in disease.

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