Yale Scientists Find Telltale Alzheimer's Protein

As the Yale School of Medicine begins to focus greater attention on the fight against Alzheimer's and other neurological diseases, Medical School researchers working with proteins have given the investigation a shot in the arm.

Neurology professor Stephen Strittmatter published a paper in the February issue of the Journal of Neuroscience that identifies the protein NogoReceptor as a key factor in combating Alzheimer's disease. Strittmatter and his team observed that an increase in this protein has been shown to reduce the amount of disease-causing plaque in the brains of transgenic mice, animals that have been genetically altered to develop the neurodegenerative disorder.

Strittmatter, whose research primarily focused on nerve-spinal growth and axons -- the ends of neurons that conduct nerve impulses -- said he was originally attempting to determine how to stimulate nerve fibers to regrow after spinal cord injury.

But what he found, along with his colleagues, was that there were two key proteins at work in this mechanism.

"Nogo and NogoReceptor are proteins that stop axons from growing," he said. "There are ways to pharmacologically disrupt the interaction between [the two], and when this happens, the animals recover and the axons grow back."

This new knowledge, coupled with existing knowledge that nerve fibers and axons are important to Alzheimer's, led Stittmatter's team to question whether the NogoReceptor protein has anything to do with the protein buildup that is believed to be the culprit in provoking the onset of Alzheimer's disease.

"The first question we asked was whether the amyloid-beta peptide, [the protein] commonly thought to be the cause of Alzheimer's disease, interacts with NogoReceptor in a molecular sense," he said, "The answer to that was yes. Then we asked if animals without NogoReceptor would be more or less likely to experience Alzheimer's."

Strittmatter's team found that transgenic mice, pre-designated to develop the disease, were likely to do so at an increased rate in the absence of NogoReceptor. The researchers found that the reverse was true as well: Pumping extra protein into the brain would in turn slow down the progression of Alzheimer's disease in the mice.

Psychiatry professor Christopher Van Dyck, who also serves as director of the Alzheimer's Disease Research Unit at Yale, said Strittmatter's research marks a great stride for the field.

Van Dyck said all research into treatment and prevention for Alzheimer's is hugely important worldwide because as the global population ages, the disease will become more widespread. By the year 2030, he said, the population of Alzheimer's patients is likely to double, and by 2050, it could triple.

"Alzheizmer's is a massive public health problem," Van Dyck said. "Unless we want a society with a huge number of people that need to be cared for in nursing homes, we need to better preventative treatment."

Van Dyck, who performs clinical research, said a lot of work will have to go into applying Strittmatter's results to therapy for humans because treatments that work in mice often do not function the same way in people. Though it may seem like the obvious conclusion, Van Dyck said, effective treatment for Alzheimer's in humans may not mean pumping excess NogoReceptor into the brain.

Strittmatter said that while clinical testing is the long-term goal, there are currently no treatments that target the NogoReceptor in human beings, so all drug development will be from the ground up. He said issues of toxicity, possible side effects and drug delivery mechanisms still need to be addressed and that the protein used for the research was made from the genes of rats and must be customized for humans.

James Park MED '08 GRD '08, who, along with David Gimbel MED '08, worked on Strittmatter's team, said that though there is still a great deal of work to be done, the research they just published is extremely significant.

"We are implicating the molecule in Alzheimer's disease as another player in the disease's pathology," Park said. "We now have one additional target to consider."

Medical School Dean Robert Alpern said a research focus on Alzheimer's disease is necessary because of the growing number of people affected and the lack of knowledge of prevention and treatment methods.

"Fifty percent of people at 85 have Alzheimer's," Alpern said. "It's a devastating disease. There's been a lot of new research in the last 10 years, but we need more."

Alpern also said that the number of people afflicted with the disease is growing because, ironically, increased proficiency at treating other afflictions, such as cancer and heart disease, is gradually aging the population.