Exercise Hormone Irisin Shows Potential for Alzheimer’s Disease Treatment

New research has yielded the strongest evidence yet that irisin, a hormone discovered by Dana-Farber’s Bruce Spiegelman, PhD, that is produced in the body by muscular exercise, can by itself improve cognitive functions and potentially reverse some of the memory-destroying effects of Alzheimer’s disease.

Reporting in the journal Nature Metabolism, Spiegelman and co-authors from Massachusetts General Hospital (MGH) show in a series of animal experiments that irisin, which is released by muscles into the bloodstream following endurance exercise, reached a key area of the brain involved in memory and other mental processes and improved cognitive functions in mouse models of Alzheimer’s disease.

Irisin is a smaller portion of a protein called FNDC5 that has previously been linked with some of the health benefits of exercise. Authors of the new study say theirs is the first to show that irisin alone, which is cleaved from the FNDC5 protein as a result of muscle contractions and secreted into the bloodstream, can turn on genetic programs in the brain that bolster brain health.

“For the first time, we’ve shown that soluble irisin, and not its full-length parent protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function,” says Christiane Wrann, DVM, PhD, assistant professor of medicine at MGH and senior author of the study.

 “This is particularly important inasmuch as irisin, a small natural peptide, would be much easier to develop as a therapeutic than the much larger membrane-bound protein FNDC5,” she says. Wrann and Spiegelman hold patents related to irisin and are academic co-founders of Aevum Therapeutics. The company is developing drugs that harness the protective mechanisms of exercise to treat neurodegenerative and neuromuscular disorders.

“What makes this study particularly strong is that we show irisin’s effect on cognitive function in not one, but four different mouse models,” says Spiegelman, who is the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at Dana-Farber and Harvard Medical School.

Irisin first identified in 2012 in Spiegelman lab

It is well established that physical exercise has many health benefits, including improved cognitive functioning and delaying the onset of Alzheimer’s disease. Spiegelman and other researchers have sought molecular mechanisms that would explain how exercising muscles “talk to” various organs in the body, including the brain. These mechanisms have been elusive, but Spiegelman’s discovery of irisin in 2012 opened a new front in this endeavor. He and his group reported that the previously unknown hormone is secreted by skeletal muscles during endurance exercise. They named it irisin in reference to Iris, the Greek messenger goddess.

Bruce Spiegelman, PhD.
Bruce Spiegelman, PhD.

Hundreds of studies since then have revealed that irisin has positive effects on metabolism — turning white fat to energy-burning brown fat — and bone health, increasing bone density. Wrann, who was a postdoctoral fellow in the Spiegelman lab, found that the gene that codes for irisin is highly expressed in the brain during exercise.

“Exercise is known to have positive effects on brain health, which is why identifying key mediators of those neuroprotective benefits, like irisin, has become such a critical goal of research,” says Wrenn.

Indeed, such findings have opened a new field known as exercise mimetics, which are a proposed class of therapeutics that mimic or enhance the therapeutic effects of exercise. For example, drugs that mimic the cognitive benefits of exercise might be administered to patients who are unable to perform endurance exercise. More importantly, it is possible that such molecules given therapeutically, can affect cognitive function far more robustly than could exercise itself.

Exercise did not improve brain function in mice lacking irisin

To pin down the role of irisin alone in cognitive functioning, the researchers created mice lacking the FNDC5 protein, which prevented them from producing irisin with exercise. They then allowed these mice and mice with intact FNDC5 protein to exercise on a running wheel. The normal mice showed improved cognitive function as a result of exercise, while those in which irisin was “knocked out” did not improve their brain power by exercising. Next, they administered irisin directly into the animals’ brains. After receiving irisin, both the knockout mice and the control mice showed improved cognitive performance. This highlighted the effect of irisin on brain health.

In another crucial experiment, the scientists delivered the gene for irisin into the livers of mice that had been genetically altered to have a condition mimicking Alzheimer’s disease. The delivery of the irisin gene caused the animals’ livers to produce irisin, and the irisin hormone was secreted into the bloodstream. Two months later, the Alzheimer-model mice performed better on cognitive tests than Alzheimer mice that did not receive the irisin gene therapy. This demonstrated that the irisin hormone produced by the rodents’ liver was able to circulate through the body and cross the blood-brain barrier into the rodents’ brains.

Irisin treatment improved Alzheimer’s symptoms

Moreover, even mice with advanced stages of Alzheimer’s, whose brains showed signs of changes typical of the disease, performed better on memory tasks after treatment with irisin. The scientists noted that this was especially significant because patients with Alzheimer’s dementia typically don’t receive treatment until they have already exhibited symptoms of the disease.

An intriguing finding of the experiments was that the Alzheimer’s model mice treated with irisin had a reduction in inflammation of nerves in the brain — a hallmark of Alzheimer’s disease and other dementias.

“It’s hard to imagine anything better for brain health than daily exercise, and our findings shed new light on the mechanism involved: protecting against neuroinflammation, perhaps the biggest killer of brain neurons as we age,” says Rudolph Tanzi, PhD, co-director of the McCance Center for Brain Health at MGH.

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