Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of
Lay Summary
Abstract “Summary”
- Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) protein in the brain.
- Physical exercise has been shown to reduce Aβ burden in AD mouse models, but the underlying mechanisms are not fully understood.
- Irisin is an exercise-induced hormone that is produced by the breakdown of fibronectin type-III-domain-containing 5 (FNDC5).
- In a 3D cell culture model of AD, irisin was shown to significantly reduce Aβ pathology by increasing the release of the Aβ-degrading enzyme neprilysin (NEP) from astrocytes.
- This effect was mediated by the downregulation of ERK-STAT3 signaling.
- Integrin αV/β5 acts as the irisin receptor on astrocytes and is required for irisin-induced release of NEP.
- These findings reveal 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.
In simpler terms, the study found that irisin, an exercise-induced hormone, can help to reduce Aβ pathology in the brain by increasing the release of an enzyme that breaks down Aβ. This effect is mediated by a protein called integrin αV/β5. The findings suggest that irisin could be a potential therapeutic target for AD.
Abstract
A pathological hallmark of Alzheimer’s disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aβ pathology by increasing astrocytic release of the Aβ-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, 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. 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.
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