Irisin is a hormone released mainly from muscles after exercise which increases adipose tissue energy expenditure.
Alzheimer’s disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and severe cognitive impairment.
A pathological hallmark of AD is the deposition of amyloid-beta protein in the brain.
Physical exercise has been shown to reduce amyloid-beta burden in various AD mouse models, but the underlying mechanisms have not been elucidated.
Exercise increases circulating levels of the muscle-derived hormone irisin, which regulates glucose and lipid metabolism in fat tissue and increases energy expenditure by accelerating the browning of white fat tissue.
Studies have revealed that irisin is present in human and mouse brains and that its levels are reduced in patients with AD and in mouse models of the condition.
To test whether irisin plays a causal role in the link between exercise and reduced amyloid-beta, Massachusetts General Hospital researcher Se Hoon Choi and colleagues applied the hormone to their 3D cell culture model of AD.
“First, we found that irisin treatment led to a remarkable reduction of amyloid-beta pathology,” Dr. Choi said.
“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 is an amyloid beta-degrading enzyme that has been found to be elevated in the brains of mice with AD that were exposed to exercise or other conditions leading to reduced amyloid-beta.
The researchers uncovered even more details about the mechanisms behind irisin’s link to reduced amyloid-beta levels.
For example, they identified integrin αV/β5 as the receptor that irisin binds to on astrocytes to trigger the cells to increase neprilysin levels.
Furthermore, they discovered that irisin’s binding to this receptor causes reduced signaling of pathways involving two key proteins: extracellular signal-regulated kinase (ERK) and signal activator of transcription 3 (STAT3).
Reduced ERK-STAT3 signaling was critical for irisin-induced enhancement of neprilysin.
“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 AD,” said Dr. Rudolph Tanzi, also from Massachusetts General Hospital.
The team’s findings appear in the journal Neuron.
Eunhee Kim et al. Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron, published online September 8, 2023; doi: 10.1016/j.neuron.2023.08.012