Researchers from Mass General and colleagues have learned more about how exercise benefits brain health—insights that open a promising new approach to treating Alzheimer’s disease (AD).
In a recent study in Nature Metabolism, a team led by Mass General’s Christiane Wrann, DVM, PhD, demonstrates that it is the hormone irisin, which is produced by the muscles during exercise, that confers the positive effects of exercise on the brain.
The team also found that an injection of irisin can restore cognitive function in mouse models of Alzheimer’s disease, suggesting irisin could be effective in patients who are already displaying symptoms of the disease.
“The fact that irisin treatment was effective in AD mouse models even after the development of significant pathology is promising for translation into humans, where therapy would typically start after patients are already symptomatic,” says Wrann, an investigator at the Cardiovascular Research Center and the McCance Center for Brain Health at Mass General, and an assistant professor of medicine at Harvard Medical School.
About Irisin
Irisin, the circulating form of the membrane protein fibronectin-domain III containing 5 (FNDC5), is one of the most recently discovered in 2012 by the lab of Bruce Spiegelman, PhD, at the Dana-Farber Cancer Institute and is derived from mouse skeletal muscle.
Dr. Wrann did her postdoctoral training in Spiegelman’s lab, where one of her first experiments was to measure irisin levels in different tissue samples. When she found high levels of irisin in brain tissue, she started thinking about a potential connection between irisin and the positive cognitive effects of exercise.
To investigate these connections, Wrann and her research team conducted a series of experiments with mice that were genetically engineered to remove—or “knock out”—the gene that codes for FNDC5 and thereby irisin (KO mice). They compared these KO mice to wild type mice (mice without any genetic alterations).
Exercise & Irisin
Running exercise has been shown to improve spatial learning and memory, even in young mice, and is a key factor for enhancing cognitive function and the generation of new neurons in the hippocampus.
Both wild type mice and the KO mice exercised the same amount with voluntary free wheel running, but only the wild type mice showed exercised-induced improvements in memory and performance during subsequent tests in a water maze.
The mice in both groups were also given a pattern recognition test, in which they are trained to recognize subtle differences between two scenarios. While the KO mice performed significantly worse than the KO mice at baseline, their performance was improved when they received surgical injections of irisin in the brain.
Aging & Irisin
To test how a lack of FNDC5/irisin affects mice as they age, the researchers used the novel object recognition test, a common measure of cognition.
The test takes place over two sessions. In the first session, the mice are introduced to two objects. In the second test, one of the objects is replaced with a different one. Cognitively healthy mice typically spend more time exploring the new object, recognizing that they have not seen it before.
Wrann and her team gave the novel object recognition test to both the KO and the wild type mice. When the test was given to young mice (8-10 weeks old), both groups preferred the novel object during the second session. However, in aged mice (21-24 months), the KO mice showed no preference for the new object during the second session, suggesting a diminished ability to recognize differences.
Alzheimer's Disease & Irisin
In separate experiments using AD mice (mouse models genetically engineered to develop an inherited form of Alzheimer’s disease) the team tested the effects of irisin injections (or irisin treatment) on cognitive performance. Eight-month-old AD mice, which were already displaying the cognitive deficits of AD, received injections of a viral vector designed to increase irisin production in the liver to reach pharmacological irisin levels in plasma.
At 10 months of age, irisin-treated AD mice performed significantly better in spatial learning and memory tests and showed improved context discrimination and pattern separation.
Irisin and Adult-Born Neurons
To learn how irisin affects the growth and maturation of adult born neurons in the hippocampus, the team injected both the exercised and non-exercised wild type and the KO mice with a fluorescent reporter virus.
Although the KO mice increased the number of adult-born neurons after exercise, same asthe wild type mice, these neurons lacked an exercise-induced increase in dendritic complexity, had smaller and lesser dendritic spines, and displayed abnormal functioning—defects that are all consistent with impaired maturation.
This suggests that irisin plays a role in the pruning and integration of new neurons into existing neuronal circuits, says Wrann.
“In neurobiology, it’s not always good to have more—you have to have the right amount,” she explains. “If you have too little and you can’t talk to your neighbor, that’s not good. If you have too many and everyone is like yelling in your ear, that’s not good.”
Pathway to a Treatment
While the findings are promising, more research needs to be done before irisin can start being tested as a treatment for patients.
“We want to do everything we can to get this into the therapeutic realm,” says Wrann, the co-founder of a company developing irisin-based treatments for AD. “We’ve done a lot of very careful studies, and I’m cautiously optimistic that we can do that.”
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