BioEd Online

Mice with memory loss have had their condition reversed, a discovery that should help refine the search for a cure for Alzheimer's disease and other dementias.

The study also helps clarify the actual cause of dementia, which should give more focus to drug studies.

The brains of people with Alzheimer's and some 50 other forms of dementia are known to have certain characteristic features, including messy bundles of fibres in nerve cells called neurofibrillary tangles. But no one has been sure whether the tangles are a cause or symptom of dementia.

Mice engineered to massively overproduce a protein called tau tend to grow more of the tangles and display the same problems with memory and learning as humans with dementia. Researchers think that it is a certain version of the tau protein, rather than a simple over-abundance, that leads to the tangles.

It has been speculated that these tau proteins, rather than the tangles, kill nerve cells.

Untangling the cause

Karen Ashe, a neurobiologist at the University of Minnesota Medical School in Minneapolis, and her colleagues hoped to untangle this mystery.

They trained mice to navigate a maze partly submerged in water, and watched for signs of memory loss. By the age of three months, mice genetically engineered to express 13 times too much tau protein couldn't remember the route to dry land, and had developed tangles in their brains.

But surprisingly, when the researchers turned off the switch promoting tau expression, the mice began to gain back some lost memory. "To tell you the truth, I expected them not to be able to get better," Ashe says.

The team reports in Science¹ that the performance of the 'switched-off' engineered mice was roughly half as good as their normal counterparts, and twice as good as those that continued to overproduce tau. And their performance improved even through the tangles in their brains remained.

Paired proteins

The results indicate that some variety of tau proteins, and not the tangles it promotes, is responsible for dementia-related memory loss.

But researchers are not yet sure which version of tau protein cause problems in the brain. That's the next step, says Ashe: "We have to figure out the molecular form of tau that is poisoning the neurons." That should give drug developers a better understanding of the molecules they should target.

But researchers caution that in the context of dementia, this is just half the story. Alzheimer's patients also have plaques in their brains made of a protein compound called beta-amyloid. Most think that this also plays a role in causing memory loss. "This is a two-protein disease," says Ashe.