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

A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-ß protein (Aß) in the brain. Physical exercise has been shown to reduce Aß 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 Aß pathology by increasing astrocytic release of the Aß-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, we show that integrin aV/ß5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aß. Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aß pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD Overall design: To compare transcriptional differences in a cell type specific manner, we performed single cell RNAseq based on the conditions below; AD + PBS + IgG; AD + irisin + IgG; AD + irisin + integrin aV/b5 antibody.