Researchers led by a team at Massachusetts General Hospital (MGH) used a 3D human cell culture model of Alzheimer’s disease (AD) to identify a cellular and molecular mechanism by which the exercise-induced muscle hormone, irisin, may prevent build up of the amyloid-beta (Aβ) deposits that are characteristic of AD pathology. The studies, led by Se Hoon Choi, PhD, and Eun Hee Kim, PhD, of the Genetics and Aging Research Unit at MGH, and reported in Neuron, suggest that irisin-based therapies may help to combat AD. In their paper, titled “Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling,” the team concluded, “Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aβ pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD.”

Alzheimer’s disease is the most common form of age-related dementia, and is characterized by progressive memory loss and severe cognitive impairment, the authors wrote. “A pathological hallmark of Alzheimer’s disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain.” And while physical exercise has been shown to reduce amyloid-β deposits in various mouse models of AD, the mechanisms involved have remained a mystery. As the team continued, “Physical exercise has been shown to diminish various aspects of AD pathology in animal models, including cerebral Aβ levels and amyloid deposition and neuroinflammation, leading to amelioration of cognitive dysfunction.”

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 neurodegenerative disorder. “Recently, it has been reported that irisin levels are reduced in the hippocampus and cerebrospinal fluid (CSF) of AD patients as well as in the brains of AD mouse models,” the researchers pointed out.

The MGH team had previously developed the first 3D human cell culture model (the 3D-AD model) of Alzheimer’s disease that exhibits generation of amyloid-β deposits, followed by tau tangles, which are the two major hallmarks of the condition AD. For their reported study, together with their collaborators, the researchers used this model to investigate whether the exercise-induced muscle hormone irisin plays a causal role in the link between exercise and reduced amyloid-β.

The 3D-AD cultures consist of neurons, astrocytes and oligodendrocytes, and the team found that found that irisin significantly reduces Aβ pathology by increasing the release, by astrocytes, of the Aβ-degrading enzyme neprilysin (NEP). Elevated neprilysin levels had previously been found in the brains of mice with AD that were exposed to exercise or other conditions leading to reduced amyloid-β.

The researchers then uncovered further details about the mechanisms behind irisin’s link to reduced amyloid-β levels. They identified integrin αV/β5 as the receptor that irisin binds to on astrocytes to trigger the cells to increase secreted neprilysin (secNEP) levels. “… we show that integrin αV/β5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aβ,” they noted. Interestingly, genetically or pharmacologically inhibiting αV/β5 alone led to decreased levels of alpha-β proteins in the 3D-AD cultures.

The team also discovered that irisin binding to the αV/β5 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. “We found that ERK inhibition significantly reduced the levels of total and phosphorylated STAT3 in the 3D-AD cultures, accompanied by increased secNEP activity/levels in the media,” the team stated. These results, they noted, suggest that STAT3 signals downstream of ERK and that ERK inactivation results in increased NEP secretion from astrocytes by inhibiting STAT3.

“First, we found that irisin treatment led to a remarkable reduction of amyloid beta pathology,” said 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.”

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.”

Previous studies have shown that in mice, irisin injected into the bloodstream can make its way into the brain, making it potentially useful 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,” said co-senior author Rudolph Tanzi, PhD, director of the genetics and aging research unit.

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