U of M research offers new hope for Alzheimer's treatment

For the past 100 years, researchers have focused their attention on two noticeable features in the brains of patients with Alzheimer's disease - neurofibrillary tangles and plaques. Tangles are abnormally twisted fibers that build up inside of nerve cells. Plaques are hard deposits of protein fragments that form on the outside of nerve cells.

Scientists believed these plaques and tangles caused Alzheimer's disease because these features don't occur in healthy brains.

But last summer, a U of M research team lead by Karen Ashe, a Professor of Neurology, proved that neurofibrillary tangles do not cause memory loss in mice. The team's latest research shows that plaques don't cause the condition either.

Instead, Ashe says memory loss is caused by a rare, toxic form of a naturally-occuring brain protein.

"This is exciting because we've isolated something out of the brain that actually impairs cognitive function," she says.

The protein impairs brain function by slowly poisoning the brain over time. Ashe named the substance A-Beta Star.

What Dr. Ashe has done, which no one else had done, was to purify the poison, transfer it to a healthy animal and cause the memory defect in the healthy animal.

She says locating the protein was like searching for a needle in a haystack. That's because A-Beta Star is an extremely scarce protein compared to the many other forms of A-Beta protein that exist in the brain. To identify A-Beta Star, one of Ashe's researchers painstakingly sorted through and catalogued the A-Beta protein forms he could find. "He separated them into those which were found inside neurons and those which were found outside neurons, those which were associated with membranes that encompass cells and those which were found in the plaques. Out of all those different A-beta types he identified one which correlated very, very strongly with memory problems in mice," she says. But Ashe and her team still had to prove that this particular protein variation caused memory loss or dementia in the mice.

"Just finding something correlating isn't the same as showing that it's causing memory problems," she says. "So the next thing he did was he purified it from the brains of impaired mice and then it was injected in a purified form into young healthy animals."

After the A-Beta star protein was injected into those health animals, they developed memory problems too.

Like Ashe, other Alzheimer researchers have long suspected that a form of A-beta protein causes memory loss. But Dr. Sam Gandy, Chair of the Medical and Scientific Advisory Council for the Alzheimer's Association, says Ashe was the first to prove it.

"What Dr. Ashe has done which no one else had done, was to purify the poison, transfer it to a healthy animal and cause the memory defect in the healthy animal. So while others also had part of the story right, they were right. But it was only part of the story."

Gandy says now that Ashe has identified a toxin responsible for memory loss in mice, researchers can start developing drugs that specifically target the faulty protein in humans. Already there's considerable optimism about their prospects for success.

Previous rodent studies have shown that researchers can actually restore memory function in mice with memory loss. That could mean that Alzheimer's diseases could be reversed in humans if it's caught early enough.

Gandy says this is news that doctors, families and patients have been hoping to hear for a long time.

"Now having said that...we must also remind families that these are just mouse studies and they have to be extended to humans to find medicines that will work in humans. We can't tomorrow immediately have a medicine. But now we are on the right track to looking for it."

This means that Alzheimer treatments might be within reach in as little as three years. Gandy says it's possible. So does Karen Ashe.

Ashe was recently named director of the new Center for Memory Research and Care at the University of Minnesota. Ashe says the center will use research from her lab to develop new drugs in collaboration with the University's Department of Medicinal Chemistry.

The center will also open a memory clinic in the next few months that offer researchers an opportunity to test new drugs on patients who are willing to participate in human trials.

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