Strategy Could Put Brakes on Alzheimer's

In mice, lowering levels of a brain protein kept memory alert

THURSDAY, May 3, 2007 (HealthDay News) -- By cutting levels of a brain protein called "tau," scientists were able to preserve the memory and lifespans of mice genetically engineered to develop Alzheimer's disease.

The finding, while early, could point to effective strategies to protect aging humans against the brain-robbing illness.

"We found a way to make brain cells in the brain more resistant to poisonous amyloid protein that builds up in the brain," explained study senior author Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease and professor of neurology at the University of California, San Francisco.

"The trick we used was to reduce normal [tau] protein that we all make by half," Mucke said. This strategy "somehow made the cells of the brain and memory resistant to the detrimental effects of amyloid protein," he explained

One expert was impressed by the findings. "This provides scientists with a new target, or rather, re-tools a known substance into a potential drug target," said Dr. Sam Gandy, chair of the Medical and Scientific Advisory Council of the Alzheimer's Association, and director of the Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia.

The findings, reported in the May 4 issue of Science, would be a complement to current efforts to combat Alzheimer's by reducing levels of amyloid protein in the brain.

There are currently no effective treatments for Alzheimer's disease, which now affects over 5 million Americans, according to the Alzheimer's Association. Scientists now project that unless new ways are found to prevent or treat the disease, the total could climb to 16 million by mid-century.

Much current research focuses on reducing the buildup in the brain of clumps of amyloid-beta protein, which are believed to cause the disease. This strategy would complement that approach.

"I'm very enthusiastic about anti-amyloid treatment but I thought it would be very useful to have a complementary approach to make the brain more resistant to whatever amyloids you can't get rid of," Mucke explained.

In a normal brain, "tau acts to form part of the scaffolding or skeleton that gives the nerve cell its shape," Gandy said. In an Alzheimer's brain, however, the scaffolding collapses and forms "neurofibrillary tangles."

"Conventional wisdom would've predicted that tau deficiency would be a very bad thing -- and that may still be true for severe deficiencies -- but the good news is that dialing down the tau level just a small bit may be sufficient to cause this newly observed benefit," Gandy said.

In this experiment, Mucke and his team eliminated one or both copies of the tau gene in mice genetically engineered to produce amyloid proteins.

Doing so prevented the expected cognitive and neuronal deficits, the team report.

"Mice that had a brain full of amyloid could memorize things quite nicely," Mucke noted.

That effect was seen even when tau levels were cut in half, rather than completely eliminated.

At this point, the researchers aren't entirely sure how this strategy succeeds.

"We think tau reduction acts a little bit like a restrictor plate on a race care, which prevents it from spiraling out of control," Mucke explained. "That's what happens to some nerve cells when they become overexcited by amyloid protein or by a variety of other factors. This is 'excitotoxicity' -- too much excitation of nerve cells. Reducing tau seems to prevent that from happening."

Excitotoxicity has been implicated in a variety of neurological diseases. This paper also showed that reducing tau made mice less prone to having epileptic seizures, for instance.

"There are potentially broad applications," Mucke said.

"The fact that this implication involves three major morbidities (Alzheimer's, stroke, epilepsy) will undoubtedly make for a great synergy of effort, since it is conceivable that from any one line of research could emerge a truly broad spectrum neuroprotectant," Gandy added.

More basic research needs to be done before the strategy can be applied to humans, but Mucke believes it's a promising avenue.

"My view is that we are not going to treat Alzheimer's with one drug," he said. "It's very important that we don't put all our money into anti-amyloid treatment but that we diversify a little bit. I think tau is a worthy target."

More information

Learn more about Alzheimer's at the Alzheimer's Association.

SOURCES: Lennart Mucke, M.D., director, Gladstone Institute of Neurological Disease, and professor, neurology, University of California, San Francisco; Sam Gandy, M.D., Ph.D., chairman, Medical and Scientific Advisory Council, Alzheimer's Association, and director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia; May 4, 2007, Science
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