This protein, which normally occurs in the body, can change shape in several ways, he says. It can take a hairpin shape and form fibers called amyloid plaques, which are found in the brains of patients with Alzheimer’s. Or it can morph into free-floating protein clumps called oligomers, also found in the brains of those with Alzheimer’s disease.
“These clumps ... seem to be more toxic to the brain,” Gandy says. He now thinks the oligomers, not plaques, cause the loss of memory and reason that characterize Alzheimer’s. Gandy and colleagues published their work in the Annals of Neurology in April 2010. Dillin, of the Salk Institute of California, started pursuing the same oligomer theory several years ago. Then the idea was so controversial, Dillin says, that some scientists would walk out of the room when he made his presentation at conferences. Now, he says, many of the top researchers in the field are convinced.
A plaque-free mouse
Alzheimer’s disease is characterized by two main elements — the sticky amyloid plaques that form outside the brain cells, and tangles of another protein, tau, that twist around the inside of the brain cells. Both are thought to play a role in the progression of the disease.
Scientists noticed the buildup of the sticky plaques in the brains of people with Alzheimer’s disease 100 years ago. And although there has been some debate, the prevailing science has held that sticky plaques and tau tangles cause Alzheimer’s.
Then, in 2004, scientists described mice that had no plaque but nevertheless showed signs of dementia. Other scientists showed that injecting rats with the oligomers caused memory loss. Another lab conducted an experiment to turn oligomers into plaques — they’re made of the same protein — and “when they did this gene trick, the mice got better, their memory improved,” Gandy says.
So Gandy and his colleague Michelle Ehrlich, M.D., also a professor at Mount Sinai, genetically engineered a new type of mice whose brains produce only oligomers but never brain plaques.
“Sam has done the most elegant experiments that really put the nail in the coffin” of the older, more widely accepted plaque theories, says Dillin.
Not only did these new mice lose their memories, but after their deaths the researchers found mice with the worst memory had the highest oligomer levels.
Oligomers “should be enemy number one,” agrees Rudolph Tanzi, director of the Genetics and Aging Research Unit at Massachusetts General Hospital, an Alzheimer’s scientist and author of Decoding Darkness: The Search for the Genetic Cause for Alzheimer’s Disease.
Are plaques brain pearls?
The plaques and oligomers are originally formed from the same protein that is found throughout the body. These proteins break down naturally in the body throughout our lives. But Tanzi and others suspect that as the body ages, too many of these protein clumps, the oligomers, create a damaging buildup in the brain. They also may trigger the creation of tau tangles that gum up the brain’s signaling system.