Alzheimer's may be handiwork of 'prion' proteins: A-beta moves from cell to cell, spreading destruction.

A protein implicated in Alzheimer's disease travels directly from one brain cell to another, damaging the cells in ways that could lead to dementia, a new study shows. Such spreading may be extra dangerous because the protein, amyloid-beta, seems to have the prionlike ability to convert its harmless form into a toxic version, other new work suggests.

Together, the results cast the cellular events of Alzheimer's in a new light, offering a view that may ultimately lead to effective ways of interrupting the devastating disease.

The two studies add to the argument that A-beta is a prion like the contagious culprits behind Creutzfeldt-Jakob disease, mad cow disease and scrapie in sheep. A prion's misfolded, toxic form can induce misfolding in other proteins, leading to disease. There's no evidence that Alzheimer's can spread from person to person, but thinking of it as a prion disease could change the way researchers approach treatments and prevention.

In one of the studies, researchers injected purified A-beta protein into one side of mice's brains and monitored the protein with a fluorescent molecule that became visible as the A-beta accumulated. After about 300 days, the A-beta had piled up throughout the brain, similar to what happens in Alzheimer's, the scientists report online June 18 in the Proceedings of the National Academy of Sciences. "It really does spread," says study coauthor Kurt Giles of the University of California, San Francisco. "We inoculate in one part of the brain, but the pathology spreads through the whole brain."

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The most devastating A-beta, the team found, was the kind taken directly from other mice's brains and purified. But a synthetic kind made in the lab also spread, albeit slower than brain-derived A-beta. Previous studies have hinted that A-beta acts like a prion, but no one had successfully shown that, on its own, synthetic A-beta could seed widespread A-beta deposits. Presumably, that occurs as misfolded forms convert the brain's native A-beta into harmful versions. By demonstrating that synthetic A-beta can kick off the spread, researchers nailed that A-beta can act as a seeding agent, says neurobiologist Mathias Jucker of the University of Tubingen in Germany. "It's very, very beautifully shown."

Neuroscientist George Bloom of the University of Virginia in Charlottesville points out that the study doesn't rule out an alternative explanation for the effect of the A-beta inoculations. The extra A-beta could be changing the flux of A-beta production or clearance, which would then result in A-beta accumulation. But the data are convincing, he says. "It sure looks and smells a lot like prion disease."

The UCSF team didn't have the resolution to see exactly how the A-beta spread through the brain, nor did the team know which form the prionlike A-beta took. But results from another new study, published June 27 in the Journal of Neuroscience, help answer both of these questions.

Martin Hallbeck of Linkoping University in Sweden and colleagues caught A-beta moving directly from inside one nerve cell to the inside of another in a dish. A-beta flowed from a cell chock-full of A-beta to a healthy cell via long cellular tendrils akin to nerve cells' message-moving axons and dendrites, the team found. Both rat and human cells showed this A-beta transfer, visible because the researchers manipulated A-beta so that it glowed red under the microscope.

As A-beta began to pile up in previously amyloid-free cells, the researchers saw signs of cellular deterioration, such as ominous shape changes and leaky organelles. "For the first time, we show that A-beta can be spread from one neuron to the next through connections, and the receiving neuron will start to deteriorate," says Hallbeck.

In these experiments, A-beta proteins were arranged in oligomers, a form that's smaller and less sticky than the plaques visible in the brains of people with Alzheimer's. Some scientists have suggested that oligomeric A-beta is the truly dangerous form. And location matters, too. Hallbeck and colleagues' data suggest that in its oligomer form, A-beta causes damage by actually invading the cell, as opposed to triggering harmful changes from outside nerve cells, says Bloom.

"This is the strongest evidence to date that intracellular accumulation of amyloid oligomers maybe toxic" Bloom says.

Hallbeck and his team couldn't tell whether their glowing A-beta was able to convert harmless forms of the protein in the cells into toxic species, as would be expected if the protein was behaving as a prion. But the team hopes to develop a way to tell the difference between its tweaked A-beta and cells' natural stores.

More experiments will be needed to reveal the 3-D shapes of the A-beta molecules, and how those conformations may change. But having a deeper understanding of how A-beta moves through the brain will help scientists develop ways to halt that process, Hallbeck says. "The implications are quite large," he says. "With this knowledge, we can start looking for ways to block A-beta transfer between cells. That'll be a way to stop the spread of the disease."

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In addition to pointing out ways to interfere with the disease, the idea that A-beta is a prion also raises troubling implications for people who participated in a clinical trial in which they received a form of A-beta made in the lab, Giles and colleagues write in their paper.

In a clinical trial halted in 2002, people with mild to moderate Alzheimer's were immunized with synthetic A-beta in an effort to clear their brains of A-beta buildup. If synthetic A-beta behaves like a prion, these people could face a heightened risk for A-beta buildup, the researchers propose. There's currently no evidence of this, says pathologist Eliezer Masliah of the University of California, San Diego. "Even though it's something to be aware of, I think the likelihood of that is very small."