Exercise-induced hormone irisin may reduce Alzheimer’s disease plaque and tangle pathology in the brain

Researchers who previously developed the first 3D human cell culture model of Alzheimer’s disease (AD), which exhibits two key hallmarks of Alzheimer’s disease (AD): amyloid-beta deposition followed by tau tangle formation, now Using that model, we investigated whether exercise-induced muscle influences Alzheimer’s disease (AD). The hormone irisin influences amyloid-beta pathology.

as reported in the magazine neuronA team led by Massachusetts General Hospital (MGH) has found promising results suggesting that irisin-based treatments may help fight Alzheimer’s disease.

Physical exercise has been shown to reduce amyloid-beta deposition in various mouse models of Alzheimer’s disease, but the mechanisms involved remain enigmatic.

Exercise increases circulating levels of the muscle-derived hormone irisin. Irisin regulates glucose and lipid metabolism in adipose tissue and increases energy expenditure by promoting browning of white adipose tissue.

Studies have revealed that irisin is present in human and mouse brains, with reduced levels in Alzheimer’s disease patients and mouse models of Alzheimer’s disease.

To investigate whether irisin plays a causal role in the association between exercise and amyloid beta reduction, Se Hoon Choi, PhD, Eun Hee Kim, PhD, MGH’s Genetics and Aging Research Unit, along with additional colleagues. , applied this hormone to a 3D cell culture model of Alzheimer’s disease.

“First, we found that irisin treatment significantly reduced amyloid-beta pathology,” Choi said. “Second, we have shown that this effect of irisin is due to increased neprilysin activity due to increased levels of neprilysin secreted by cells in the brain called astrocytes.”

Neprilysin is an amyloid-beta degrading enzyme that has been found to be elevated in the brain of AD mice exposed to exercise and other conditions that lead to amyloid-beta depletion.

The researchers have revealed more details about the mechanism behind the association between irisin and lower amyloid beta levels. For example, they identified integrin αV/β5 as the receptor through which irisin binds to astrocytes, causing an increase in cellular neprilysin levels.

Furthermore, they found that irisin binding to this receptor reduced signaling in a pathway involving two key proteins, extracellular signal-regulated kinase (ERK) and activator of transcriptional signal 3 (STAT3). discovered. Reduction of ERK-STAT3 signaling was critical for the potentiation of neprilysin by irisin.

Previous studies have shown that irisin injected into the bloodstream of mice can reach the brain and serve as a therapeutic agent.

“Our results show that irisin is the primary mediator of exercise-induced increases in neprilysin levels, leading to a reduction in amyloid-β burden, and a novel therapeutic target for the prevention and treatment of Alzheimer’s disease. suggesting a pathway,” says Dr. Rudolf Tanzi. is the senior author of this study and director of the Genetics and Aging Research Unit.

Additional co-authors include Hyeonwoo Kim, Mark P. Jedrychowski, Grisilda Bakiasi, Joseph Park, Jane Kruskop, Younjung Choi, Sang Su Kwak, Luisa Quinti, Doo Yeon Kim, Christiane D. Wrann, and Bruce M. Spiegelman. Masu.