Team collars an accessory to Alzheimer's: supposedly harmless prions conspire in brain disease.
In mad cow and Creutzfeldt-Jakob diseases, misshapen prion proteins do the damage. But the new paper, published in the Feb. 26 Nature, offers evidence that the supposedly harmless version of the prion protein assists the amyloidbeta protein responsible for brain cell death in Alzheimer's disease.
"It's pretty sensational," comments Adriano Aguzzi of the University of Zurich. "What's tremendously electrifying is that prion protein may be a ... sensor for extremely toxic, small concentrations of A-beta."
A-beta proteins can travel alone or in groups in the brain. On their own, A-beta proteins are harmless. Massive, insoluble clumps of A-beta, known as plaques, are probably harmless too, says study coauthor Stephen Strittmatter of Yale University. These plaques may be a gravestone marker of dead brain cells but are probably not the killer.
Instead, smaller, soluble clumps of 50 to 100 A-beta proteins, known as oligomers, are the most likely suspect, says Strittmatter. Earlier studies have shown that mice with A-beta oligomers don't move through a previously learned maze as quickly as mice without active A-beta oligomers. Such oligomers prevent cross-talk between brain cells in the mouse hippocampus, which could help explain the loss of learning and memory in people with Alzheimer's disease.
But how these A-beta oligomers cause cellular mayhem is not known. At very low concentrations the oligomers are toxic to cells, so it's likely that specific proteins on cells are exquisitely tuned to recognize the A-beta proteins, Strittmatter says.
"What's been unclear is if A-beta acts on cells directly or if it acts through cell surface receptors, where it maybe corrupts the cell in some way," comments Lennart Mucke of the Gladstone Institute of Neurological Disease in San Francisco and the University of California, San Francisco, who wrote a commentary in the same issue of Nature.
Strittmatter and his colleagues searched for proteins embedded in the outer membranes of cells that might sense the dangerous A-beta oligomers. After screening 225,000 possible mouse proteins, only one specifically grabbed on to oligomers of the human form of A-beta: the prion protein.
The role of the harmless prion protein, which is prevalent in the brain and peripheral tissues of healthy people and animals, has been a mystery. "Everybody and his brother have been trying to find the normal function of prion protein," Aguzzi says.
Earlier reports suggest that the protein may help maintain the brain's white matter, control brain cell formation and have a role in sensing smells. Even so, Aguzzi says, the protein's role is far from settled. "I never had the feeling that we've come to the bottom" of its function, he says. But prion protein's new job as an A-beta oligomer sensor may shed light on how A-beta proteins can damage brain cells.
In the new study, researchers looked at hippocampal brain cells taken from mice that produced no prion protein as a middleman. When the team washed A-beta oligomers over the prion-free brain cells, the oligomers did not affect a type of cell-to-cell signaling important in learning. Researchers got similar results in normal brain cells using an antibody to block the 11-amino-acid stretch of the prion protein required for A-beta binding. These "striking" results make the case that prion proteins are crucial for A-beta-induced damage, Mucke says.
Blocking prion protein binding maybe a new therapeutic approach for Alzheimer's disease. "In many ways it maybe better than addressing A-beta levels," which are difficult to reduce completely, says Strittmatter.
Researchers don't yet know if prion protein and A-beta interact similarly in human Alzheimer's disease, or if blocking the interaction would be effective or safe in humans.
"Every new discovery raises more questions than it answers," Mucke says.
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|Title Annotation:||Body & Brain|
|Date:||Mar 28, 2009|
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