Supposedly harmless version plays a role in neuron malfunction
Prion protein, notorious for causing the brain-wasting mad cow and Creutzfeldt-Jakob diseases, may also be a coconspirator in Alzheimer’s disease, a new study in mice suggests.
In mad cow and Creutzfeldt-Jakob diseases, misshapen prion proteins do the damage. But the new paper, appearing February 26 in Nature, offers evidence that the harmless version of the prion protein assists the amyloid-beta protein responsible for brain cell death in Alzheimer’s disease.
“It’s pretty sensational,” comments Adriano Aguzzi, a neuropathologist at the University of Zurich. “What’s tremendously electrifying is that prion protein may be a genetic 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, a neuroscientist at 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, Strittmatter says.
Earlier studies have shown that mice with A-beta oligomers can’t remember how to get through a maze as quickly as mice without A-beta oligomers. Such oligomers prevent cross-talk between certain brain cells in the hippocampus of mice, which helps explain the loss of learning and memory functions in Alzheimer’s disease.
But how these A-beta oligomers cause cellular mayhem is a mystery. The oligomers are toxic to cells at very low concentrations, so it’s likely that specific proteins are exquisitely tuned to recognize the A-beta proteins. “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, a neuroscientist from the Gladstone Institute of Neurological Disease in San Francisco and the University of California, San Francisco, who wrote a commentary in the same Nature issue.
Strittmatter and his colleagues searched for proteins embedded in the outer membrane of cells that might sense the dangerous amyloid-beta oligomers. After screening 225,000 possible mouse proteins, only one specifically grabbed on to the human form of A-beta: the prion protein. The protein bound to oligomers but not to single A-beta proteins.
The role of 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 and brain cell formation, and may have a role in sensing smells. Even so, Aguzzi says, the matter is far from settled. “I never had the feeling that we’ve come to the bottom of [prion protein’s] function,” Aguzzi 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 removed the prion protein middleman from mice and examined brain slices. When the team washed A-beta oligomers over the brain slices, the oligomers no longer had an effect on cell activity in the hippocampus. The researchers got the same results when an antibody blocked the 11 amino acids of prion protein required for A-beta binding: no harmful A-beta effects. These “striking” results make the case that prion proteins are crucial for A-beta–induced damage, Mucke says.
Blocking prion protein binding may be a new therapeutic target for Alzheimer’s disease. Get rid of the prion protein middleman, or its ability to bind A-beta oligomers, and get rid of the disease. “In many ways it may be better than addressing A-beta levels,” which are difficult to reduce completely, Strittmatter says.
The research is in very early stages. “Every new discovery raises more questions than it answers,” Mucke says, and these findings are no exception. Researchers don’t yet know if prion protein and A-beta interact similarly in human Alzheimer’s disease, or if blocking the connection between prion protein and A-beta is effective or safe in humans.
“How A-beta makes neurons sick was a black box,” Strittmatter says. “This research helps us understand the first step of the process.”
Laure´n, J., et al. In predd. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-b oligomers. Nature. doi:10.1038/nature07761