Super-fit mice reveal anti-inflammatory protein that could boost search for Alzheimer's drugs

What happens when a three-month-old mouse racks up more than four miles a day exercising on his running wheel? His body produces a protein that tamps down inflammation in the brain. That discovery, from Stanford University’s School of Medicine, could inspire new treatments for Alzheimer’s and other neurodegenerative diseases, the researchers suggested.

The Stanford team found that when they took blood from the young “marathoner” mice and injected it into sedentary mice, the latter group showed improvements in brain health. They went on to discover that a protein called clusterin was more prevalent in the exercising mice and was largely responsible for the anti-inflammatory brain-boosting effects of the blood injections, they reported in Nature.

The researchers started their experiment by comparing young mice that had unlimited access to a running wheel to those that didn’t. They then gave some of the sedentary mice blood from the marathoner mice and put all the non-running mice through two memory tests.

The treated mice outperformed the controls on those tests. “The runners’ blood was clearly doing something to the brain, even though it had been delivered outside the brain,” said Tony Wyss-Coray, Ph.D., professor of neurology and neurological sciences at Stanford, in an article posted by the university.

The Stanford team went on to study more than 200 proteins in the blood of the super-fit mice. They found 26 that were more prevalent in the exercising mice. Several of those proteins were associated with the “complement cascade,” a set of proteins that prompts the immune response to foreign invaders.

That was a key discovery, because when the complement system doesn’t work properly, chronic inflammation can occur, speeding up the advance of several brain disorders, Wyss-Coray said. They zeroed in on clusterin because they found that when they removed it from the blood of the fit mice, injecting the blood into sedentary animals did not produce anti-inflammatory effects.

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Much of the Alzheimer’s research over the past several years has focused not on beneficial proteins, but rather on amyloid beta and tau, two proteins that form the toxic brain plaques and tangles seen in the disease. That continues to be the focus of several research groups, including one at the University of Houston, which recently published a study suggesting a new strategy for preventing amyloid beta peptides from forming plaques.

Wyss-Coray and his colleagues at Stanford are focused on clusterin and its effect on the complement cascade. As part of their study, they conducted experiments that showed clusterin attaches to endothelial cells that line the brain’s blood vessels. These cells are often inflamed in Alzheimer’s.

In a separate experiment, the Stanford team recruited 20 veterans with signs of cognitive impairment for a six-month exercise program. When they collected their blood after the program ended, they found elevated levels of clusterin.

Wyss-Coray concluded that a drug that reduces inflammation in the brain by mimicking the binding of clusterin to endothelial cells could prove effective in slowing Alzheimer’s and other neurodegenerative diseases.