Exercise increases circulating levels of the muscle-derived hormone. Studies have shown that irisin is present in both human and mouse brains, but levels are reduced in those with AD as well as in mouse models of the condition. To investigate the link between irisin, exercise, and reduced levels of amyloid beta the researchers applied the hormone to 3D cell culture models of Alzheimer’s disease.
“First, we found that irisin treatment led to a remarkable reduction of amyloid beta pathology,” says Se Hoon Choi, Ph.D. and Eun Hee Kim, Ph.D., of the Genetics and Aging Research Unit at MGH “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.”
The researchers report that integrin αV/β5 is the receptor that irisin binds to on astrocytes to trigger the cells to increase neprilysin levels, and binding to this receptor causes reduced signaling of pathways involving extracellular signal-regulated kinase (ERK) and signal activator of transcription 3 (STAT3): Reduced ERK-STAT3 signaling was critical for irisin-induced enhancement of neprilysin.
Neprilysin is an amyloid beta-degrading enzyme that is found in elevated levels within the brains of mice models of AD that were exposed to exercise or other conditions leading to reduced levels of amyloid beta. Previous studies have shown that when injecting irisin into the bloodstream of mice, the hormone makes its way to the brain, displaying promise as a therapeutic.
“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,” says Rudolph Tanzi, Ph.D., a senior author of the study and director of the Genetics and Aging Research Unit.
The authors concluded, “… we present the experimental data showing that irisin reduces Aβ pathology by increasing NEP activity/level secreted from astrocytes … our findings offer strong support for developing irisin as a therapeutic target to reduce Aβ burden for AD treatment and prevention.”
