Summary: The muscle-derived hormone irisin, which rises with physical exercise, may help reduce Alzheimer’s disease (AD) pathology. Using advanced three-dimensional human cell models that reproduce key AD features, researchers found that irisin treatment sharply lowers amyloid beta accumulation. This benefit appears to result from increased release of neprilysin, an enzyme that degrades amyloid beta. These findings point to irisin-related signaling as a promising therapeutic target to prevent or slow AD progression.
Key Facts:
- Irisin, a hormone elevated by exercise, can markedly reduce amyloid beta deposits that characterize Alzheimer’s disease.
- The decrease in amyloid beta is driven by higher levels of neprilysin, an enzyme that degrades amyloid beta.
- Irisin acts on astrocytes through the integrin αV/β5 receptor and suppresses ERK-STAT3 signaling, which leads to increased neprilysin release.
Source: Mass General
Researchers who created the first 3D human cell culture models of Alzheimer’s disease—models that reproduce both amyloid beta accumulation and downstream tau pathology—have now used those models to test whether the exercise-induced hormone irisin affects amyloid beta buildup.
Published in the journal Neuron, the Massachusetts General Hospital (MGH)–led team reports results that suggest irisin-based strategies may be effective in lowering amyloid beta burden and could inform new approaches for AD prevention or treatment.
Physical exercise is associated with reduced amyloid beta in several AD mouse models, but the molecular link between activity and lower amyloid burden has been unclear. Irisin, released into the circulation during exercise, is known for metabolic effects such as promoting the browning of white fat and increasing energy expenditure. Prior work has also detected irisin in the brain, and evidence indicates irisin levels decline in AD patients and in mouse models of the disease.
To test causality, Se Hoon Choi, PhD, Eun Hee Kim, PhD, and colleagues at the Genetics and Aging Research Unit at MGH applied irisin to their 3D human cell culture model of AD. Their experiments demonstrate two key findings: first, irisin treatment produced a substantial reduction in amyloid beta pathology; second, this reduction depended on a rise in neprilysin activity derived from astrocytes, the glial cells that help maintain brain homeostasis.
Neprilysin (NEP) is a major amyloid beta–degrading enzyme. Previous studies observed increased NEP in the brains of exercised mice with lower amyloid beta levels, and the new 3D cell work pinpoints a mechanism by which irisin stimulates NEP release from astrocytes.
At the molecular level, the team identified integrin αV/β5 on astrocytes as the receptor that binds irisin and initiates the response. Binding of irisin to this integrin suppresses signaling through ERK (extracellular signal-regulated kinase) and STAT3 (signal transducer and activator of transcription 3). Reduced ERK-STAT3 pathway activity was required for astrocytes to increase NEP secretion in response to irisin, which in turn promoted amyloid beta clearance in the 3D model.
Importantly, prior animal studies indicate that systemically administered irisin can cross into the brain, supporting the idea that therapeutic delivery of irisin or molecules that mimic its action might be feasible.
“Our findings indicate that irisin is a major mediator of exercise-induced increases in neprilysin levels leading to reduced amyloid beta burden,” says Rudolph Tanzi, PhD, senior author and director of the Genetics and Aging Research Unit. “This work identifies a new signaling pathway — irisin acting through integrin αV/β5 and downregulating ERK-STAT3 to boost astrocytic NEP — that could be targeted to prevent or treat Alzheimer’s disease.”
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.
Funding: This research received support from Cure Alzheimer’s Fund, the JPB Foundation, NIH grants R56AG072054 and 1R21AG062904, Coins for Alzheimer’s Research Trust, and a BrightFocus Foundation Fellowship.
About this Alzheimer’s disease and exercise research news
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: Image credit to Neuroscience News
Original Research: Open access. “Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling” by Se Hoon Choi et al., Neuron.
Abstract
Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling
Highlights
- Irisin promotes neprilysin secretion from astrocytes, driving a decrease in amyloid beta in a 3D Alzheimer’s disease cell model.
- Integrin αV/β5 functions as the irisin receptor on astrocytes and is required for neprilysin release.
- Irisin-triggered neprilysin release is mediated by downregulation of ERK-STAT3 signaling.
Summary
Amyloid-β deposition is a central pathological feature of Alzheimer’s disease. While exercise has consistently been linked to lower amyloid burden in animal models, the molecular mediators of this benefit were not fully known. Irisin, a secreted fragment of the FNDC5 protein produced by muscle during exercise, has metabolic effects and is present in the brain, where levels fall in AD.
Using a three-dimensional human cell culture model that reproduces amyloid beta accumulation and subsequent tau pathology, the researchers demonstrate that irisin markedly reduces amyloid beta by stimulating astrocytes to release neprilysin. This response requires suppression of ERK-STAT3 signaling and depends on the integrin αV/β5 receptor on astrocytes.
These results describe a clear cellular and molecular pathway linking exercise-induced irisin to enhanced amyloid beta clearance, highlighting a novel target for therapies aimed at preventing or slowing Alzheimer’s disease.