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Irisin reduces Amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling

ABSTRACT: A pathological hallmark of Alzheimer’s disease (AD) is the deposition of amyloid-β protein (Aβ) 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-domain III 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Se Hoon Choi

PROVIDER: PXD044499 | iProX | Fri Aug 11 00:00:00 BST 2023

REPOSITORIES: iProX

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Irisin reduces Amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling

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