Articles > New Approach for Alzheimers? Study offers hope.


 

New Science Sheds Light on the Cause of Alzheimer’s Disease

Researchers now looking in a new direction for a cure

 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.

The brain may try to remove the offending oligomers by forming plaques. Tanzi goes so far as to call the much-vilified plaques “brain pearls.” He says just as an oyster creates a pearl around a grain of sand to protect itself, plaques may serve as traps for microbes that are infecting the brain.

Researchers have found that some people who never had dementia nevertheless have brains coated in plaques. It may be, they theorize, that their brains were exceptionally good at converting the offending “sand” into “pearls.”

Drugs to watch

All this may help explain why research published in the British journal the Lancet in March showed that even though the new drug bapineuzumab reduced plaque in the brain, the patients failed to improve. It could also explain the failure of the once-promising Alzhemed drug that discouraged the formation of brain plaques.

Dillin fears we may even discover that drugs designed to break down plaques may speed the disease’s progression.

“I think the plaques are a sign that your brain was trying to do something very beneficial for itself in the last stages of the disease,” he says. “If you go in and take these plaques apart, you’re going to make oligomers, and that could actually be worse.”
 
On the other hand, Dillin and others say too much protective plaque buildup in the brain may in fact be harmful, interfering with brain function.

Researchers in drug development say there are several Alzheimer’s medications in the pipeline that may work with the new theory.

Tanzi says he suspects the drugs that will work to prevent the disease or at least stop its progression will not entirely destroy the oligomers—he thinks they may play an important role in the brain—but will limit their production.

“Don’t expect to hit oligomers with a sledgehammer and still have the brain be OK,” he warns. Just as statins lower but don’t totally remove cholesterol in the body, he says, we need drugs that will “dial down” the production of the oligomers.

Tanzi is the cofounder of two companies, Neurogenetic Pharmaceutical and Prana Biotechnology, which are developing drugs to do just that.

“The best drugs are yet to come,” Tanzi says. “We’re starting to see some of them in early trials. It’s hard to be patient with a disease like this, but we’ve gone through the first wave of drug failures.”

He compares the first Alzheimer’s drugs to a 10-year-old shooting a soccerball from midfield. “Now we’ve got a division one college team driving down the field.”

Not so fast

However, Thies of the Alzheimer’s Association in Chicago is cautious about the new approach to this old disease. He says it’s too soon to eliminate plaques as a drug target. The results of three clinical drug trials now in their last stages “will give us a better handle” on the role of plaques.

Theis says that it could take 10 to 15 years to develop a drug that targets oligomers rather than plaques. There’s a lot of work to be done before this research translates into real help for Alzheimer’s patients, he stresses.

Still, Thies acknowledges that this type of basic science is “critical”—and helps move researchers closer to a cure for Alzheimer’s disease.

“The fact is that without adequate support for this kind of basic science, there’s no hope,” he says.

Elizabeth Agnvall is a contributing editor with the AARP Bulletin. 

 

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