In 1906, the German psychiatrist Alois Alzheimer first described the disease that now bears his name, noting that clumps of protein known as plaques had built up between nerve cells in the brain of one of his patients who suffered from dementia. But in the century since, scientists studying Alzheimer’s disease (AD), a terminal degenerative disease that afflicts more than 26 million people worldwide, have been befuddled by the questions of what triggers plaques to begin forming in the brain in AD, and precisely how plaques may damage, and ultimately destroy, memory function.

In the February 26 issue of the journal Nature, a team from the laboratory of Stephen M. Strittmatter, M.D., Ph.D., co-director of the medical school’s Program in Cellular Neuroscience, Neurodegeneration and Repair, reported an unexpected piece in this puzzle that may lend a new direction to the next wave of Alzheimer’s research. The group found that the normal form of prion protein—the abnormal form of which is notorious for its role in mad cow disease and other neurodegenerative conditions—is one of the initial players in the disease process that leads to the deposition of plaques and dementia seen in AD.

“We had been interested in Alzheimer’s disease for a while, because a longstanding interest in my lab is recovery from various kinds of injury,” says Strittmatter, a member of Yale’s Kavli Institute for Neuroscience who is well known for his work on Nogo, a protein that blocks nerve regeneration in the injured spinal cord. “We’re interested in whether the damaged brain in Alzheimer’s could also recover in some way.”

It has long been known that Alzheimer’s plaques are large aggregations of a protein called amyloid-beta (A-β). But over the last several years, scientists have realized that A-β oligomers—much smaller, soluble structures consisting of as few as two A-β molecules—are toxic to synapses, the communication nodes of the brain, and probably represent the beginning stage in a destructive cascade that culminates in amyloid plaques.

The Strittmatter team first synthesized A-β oligomers and showed that the oligomers bound to nerve cells from the hippocampus, a brain region that is crucial to memory. The scientists then created a binding assay in which 225,000 DNA sequences from the mouse brain were expressed in nonneuronal cells, and they tested which of these sequences would bind the A-β oligomers. In a process lasting several months, “one at a time we expressed each of the genes from the brain in non-neuronal cells,” Strittmatter, the Vincent Coates Professor of Neurology and professor of neurobiology, recalls. Out of the hundreds of thousands of sequences, only one, which encodes the mouse version of the normal prion protein, bound with the oligomers. “We wouldn’t have predicted prion protein,” Strittmatter says. “We might have predicted some protein that nobody had ever studied before, one that we didn’t know anything about.”

In fact, scientists know a good deal about prion protein, because a misfolded, infectious version of the protein has been implicated in neurodegenerative diseases such as mad cow disease and Creutzfeldt-Jakob disease. “Everybody has prion protein,” Strittmatter says, adding that the protein is important for normal brain function. “But in those diseases, it changes its shape and becomes a self-replicating infectious particle, which can spread the disease to other people or animals. That infectious, twisted conformation of prion protein is not what we’re seeing in Alzheimer’s disease.”

Though the version of the prion protein studied by the Strittmatter group is not infectious, the researchers provided evidence that it disrupts memory function when bound to A-β oligomers. When brain slices from normal mice were treated with A-β oligomers, the treatment suppressed an electrophysiological process known as long-term potentiation, or LTP, which is considered to be essential to memory formation. However, brain slices of mice that lacked the gene for prion protein had normal LTP after treatment with A-β oligomers, indicating that binding with the prion protein is necessary for the oligomers to exert their deleterious effects. Though there is much to be studied to understand precisely how prion/A-β complexes damage nerve cells, “the key thing is that now we have a first step, a molecular handle,” says Strittmatter.

This “handle” may give researchers a better grip on developing new therapies for Alzheimer’s disease. With the identification of prion protein as an essential player in the disease process, scientists now have new drug targets to explore to slow or prevent the havoc A-β wreaks on the brain. “Many of the therapeutic approaches now focus on the idea that the best thing to do would be just lower the amyloid-β concentration in the brain,” Strittmatter says, adding that a new therapy may lie in preventing the interaction of A-β with the prion protein pathway. “We’re trying to develop ways to block this pathway, and then test them in animal models.”

To reach that goal, says Strittmatter, “we’d like to move to a model that’s even closer to Alzheimer’s. We’d like to prove that prion protein is required for memory loss—not just electric activity in a brain slice.” Second, Strittmatter wants to examine further the cascade of neuron damage that occurs after amyloid-b binds to prion protein. “We need to understand which genes and proteins come into play after prion protein and disrupt synaptic connections.”

“Much more work needs to be done,” says Haakon B. Nygaard, M.D., a member of Strittmatter’s lab who took part in the research along with first author Juha Laurén, M.D., Ph.D., medical student David A. Gimbel, and M.D./Ph.D. student John W. Gilbert. “But it’s nevertheless a very exciting finding, and one we hope will further stimulate current research.