Irisin-based medicines may aid in Alzheimer's disease treatment

Researchers discovered promising results indicating that irisin-based medicines may aid in the treatment of Alzheimer's disease.

The study was published in the journal Neuron.

Previously, the first 3D human cell culture models of Alzheimer's disease (AD) that displayed the disease's two primary symptoms—the production of amyloid beta deposits followed by tau tangles—were produced. The model is currently being used by researchers to see if the exercise-induced muscle hormone irisin impacts amyloid beta pathology.

Physical activity has been shown in various AD animal models to reduce amyloid beta formation, while the underlying mechanisms remain unknown.

Exercise enhances blood levels of irisin, a hormone produced by muscles that regulates lipid and glucose metabolism in fat tissue and increases energy expenditure by hastening the browning of white fat tissue.

Irisin has been found in human and mouse brains, and its levels are lowered in Alzheimer's patients and mouse models of the disease.

Se Hoon Choi, PhD, and Eun Hee Kim, PhD, of the MGH Genetics and Ageing Research Unit, together with other research colleagues, used irisin to assess if it plays a causal role in the link between exercise and lower amyloid beta.

“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.”

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 signalling of pathways involving two key proteins: extracellular signal-regulated kinase (ERK) and signal activator of transcription 3 (STAT3). Reduced ERK-STAT3 signalling was critical for the irisin-induced enhancement of neprilysin.

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 Rudolph Tanzi, PhD, a senior author of the study and director of the Genetics and Aging Research Unit.