Scientists fix rogue protein in mice that leads to Alzheimer's, brain damage

A group of Harvard scientists has figured out how to undo early damage to a protein that leads to Alzheimer's and the lasting effects of brain injuries – at least in mice. Now they are trying to do the same in people.

The researchers identified a protein that changes shape when a mouse's brain is damaged by trauma, according to a study published Wednesday in the journal Nature. They also tracked the protein as it destroyed brain cells, then found a way to return it to its useful state, the study said.

If scientists can make the process work in people – and researchers are still years away – doctors could theoretically treat people shortly after a car accident, military injury or repeated concussion on the football field to prevent psychological and behavioral problems associated with traumatic brain injuries. Doctors could also identify and treat someone at the very early stages of Alzheimer's, blocking the progression of the disease.

The study shows that brain disease can begin with very subtle changes, said Alvaro Pascual-Leone, an author on the paper, who is also a principal investigator in the Harvard Football Players Health Study.

Several scientists not involved in the study said they find the mouse work exciting, but cautioned that there is a lot more research needed before declaring victory.

"There's always some leap of faith that it will be relevant in the case of human disease," said Rudy Tanzi, a professor of neurology at Massachusetts General Hospital and Harvard and a leading Alzheimer's researcher.

David Brody, a professor of neurology at Washington University in St. Louis who wasn't involved in the study, said even if the full potential of the research doesn't pan out, this new understanding of cis P-tau helps explain the basic biology of concussion.

The study found that the brain protein tau, associated with both Alzheimer's and traumatic brain injury, takes a misshapen form after mice experience head trauma. This form, called cis P-tau, causes other tau proteins to distort, triggering a cascade of events that leads to the death of brain cells. Normal tau, Pascual-Leone said, is essential for laying down memories and learning.

The researchers developed an antibody that in mice can correct the shape of the protein, turning it back into normal tau. Researchers are searching for a similar antibody that would produce the same effect in people, said Kun Ping Lu, senior author of the paper, and chief of translational therapeutics at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, both in Boston.

Lu, who helped start a company, Pinteon Therapeutics, Inc., to design such an antibody, said it could be ready for human testing in two to three years.

The research in mice found that tau protein begins to misfold into cis P-tau immediately after a brain injury, along the outer surface of the mouse's brain. If not stopped, Lu said, it will spread deeper into the brain and cause the type of behavioral and psychological problems shown by some retired NFL players, like Junior Seau, who committed suicide in 2013.

By contrast, in Alzheimer's cis P-tau builds up from deep inside the brain, starting in the hippocampus – the seat of memory – and spreads outward, he said.

"The most exciting thing is we can do something about it. We can stop it early on," Lu said.