Boosting the exercise-induced hormone irisin in the brain could prevent plaque build up and even treat Alzheimer disease, new research suggests.

Several studies have shown that physical exercise may do more than give the heart a boost; it can also benefit the brain.

A new study says that irisin a hormone released during physical activity can reduce amyloid beta deposits and it can also be used as “a new target pathway for therapies aimed at the prevention and treatment of Alzheimer’s disease.”

Pioneering scientists, known for their groundbreaking 3D human cell culture models illustrating Alzheimer’s disease (AD) hallmarks—namely the formation of amyloid beta deposits followed by tau tangles—are delving into the effects of irisin on this amyloid beta buildup.

Published in Neuron, a study led by the Massachusetts General Hospital (MGH) team sheds light on the potential of therapies centered around irisin to counter AD.

Although it’s known that physical activity reduces amyloid beta accumulation in several AD mouse models, the exact processes remained elusive until now.

Irisin, a hormone originating from muscles, plays a part in managing glucose and fat metabolism and boosts energy expenditure by promoting the conversion of white fat. Notably, irisin is detected in both human and mouse brains, with noticeably lower levels in AD patients and corresponding mouse models.

To decipher the direct impact of irisin on the relationship between exercise and the decrease in amyloid beta, Dr. Se Hoon Choi and Dr. Eun Hee Kim from MGH’s Genetics and Aging Research Unit, together with their research team, introduced irisin to their innovative 3D cell model of AD.

“First, we found that irisin treatment led to a remarkable reduction of amyloid beta pathology,” adds Dr. Choi. “Second, we showed this effect of irisin was attributable to increased neprilysin activity owing to increased levels of neprilysin secreted from cells in the brain called astrocytes.”

Neprilysin, an enzyme that breaks down amyloid-beta, has been observed at higher levels in the brains of AD-affected mice exposed to exercise or conditions that decrease amyloid beta.

The study revealed deeper insights into irisin’s influence on amyloid beta reduction. Specifically, the team identified the integrin αV/β5 receptor, which irisin utilizes to stimulate astrocytes to produce more neprilysin. A consequential finding was that when irisin latches onto this receptor, there’s diminished activity in pathways related to two pivotal proteins: ERK and STAT3. This reduced activity of the ERK-STAT3 axis was essential for the beneficial effects of irisin on neprilysin levels.

Earlier research has demonstrated that when introduced into the bloodstream in mice, irisin can journey to the brain, hinting at its therapeutic potential.

Summarizing the study’s significance, Dr. Rudolph Tanzi, a primary contributor and the head of the Genetics and Aging Research Unit, remarks, “Our findings indicate that irisin is a major mediator of exercise-induced increases in neprilysin levels leading to reduced amyloid beta burden, suggesting a new target pathway for therapies aimed at the prevention and treatment of Alzheimer’s disease.”

Source: 10.1016/j.neuron.2023.08.012

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