Enzyme shields mice brains from the actions of a problem protein UCL CABI/Science Photo Library

Alzheimer’s disease may be prevented by stopping a crucial brain protein from turning rogue, a study in mice suggests.

Tau protein has long been suspected to play a role in causing the condition. In healthy brains, tau is essential for normal cell functioning. But during Alzheimer’s disease, the protein goes haywire, clumping together and becoming toxic. Eventually, tau forms large, twisted tangles, but it is thought that it is smaller clumps of this protein that damage the brain.

Now Lars Ittner at the University of New South Wales, Australia, and his colleagues have pinpointed a crucial enzyme that controls how tau proteins behave in the brain. The enzyme, called p38γ kinase, helps keep tau in a healthy, tangle-free state, preventing the onset of memory loss and other symptoms in mice that have been bred to develop a range of Alzheimer’s-like pathologies.


Protective effect

The enzyme seems to block symptoms of Alzheimer’s by interfering with the action of another problem protein, called beta-amyloid. Like tau, clumps of this protein accumulate in the brains of people with Alzheimer’s, making it another suspected cause of the disease.

When beta-amyloid forms these sticky plaques, it can also modify the structure of tau proteins, causing them to become toxic and form tangles. But Ittner’s team found that p38γ kinase makes a different kind of structural change to tau. If this change is made first, it prevents beta-amyloid from being able to turn tau bad, and mice do not develop Alzheimer’s-like symptoms.

In people, the levels of this enzyme decline significantly as Alzheimer’s progresses, hinting that boosting this enzyme could help prevent or treat the disease.

New approach

Using an enzyme to stop tau from becoming toxic is novel because most existing research has focused on targeting beta-amyloid, says Ralph Martins at Edith Cowan University in Western Australia.

“We’ve got treatments now that decrease beta-amyloid levels, but they don’t have much efficacy,” he says. “Animal work is increasingly showing that beta-amyloid toxicity is mediated through tau, so it’s an attractive target.”

One reason why Alzheimer’s treatments that have shown promise in mice have frequently failed in clinical trials is because earlier mouse models were designed to only mimic beta-amyloid plaque formation in humans, he says.

Ittner’s study instead used mice that were engineered to recreate the beta-amyloid-tau relationship in humans, so the results should be more applicable to people, he says. “I think this is very, very exciting. Our focus has been on beta-amyloid but this gives the tau approach a really good kick.”

Journal reference: Science, DOI: 10.1126/science.aah6205

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Correction: This article has been changed to make it clear that the toxicity of Tau proteins is the result of them forming small clumps. Clarification: This article was altered to make it clear that the mice used have symptoms similar to Alzheimer’s disease.