FNDC5/irisin expression stimulates neuroprotective pathways in hippocampal neurons and associates with Alzheimer’s disease pathology

Abstract

AbstractBackgroundIrisin is an exercise‐linked myokine produced by cleavage of the membrane precursor fibronectin type III domain‐containing protein 5 (FNDC5) in skeletal muscle, brain, and other tissues. Recently, irisin has been identified as a key molecule for exercise‐induced neuroprotection in mouse models of Alzheimer’s disease (AD). However, the role of FNDC5/irisin in AD pathology has not yet been comprehensively explored. Here, we investigated potential mechanisms underlying neuroprotection induced by FNDC5/irisin in AD.MethodPrimary rat hippocampal neuronal cultures were transduced with adenoviral vectors to express FNDC5 (AdFNDC5) or GFP (as a control) or exposed to recombinant irisin (25 nM) for defined timepoints. Brain‐derived neurotrophic factor (BDNF) levels were measured by ELISA; extracellular signal‐regulated kinase 1/2 (ERK 1/2) phosphorylation was determined by Western blotting; and the effects of irisin on amyloid‐β oligomers (AβO)‐induced reactive oxygen species (ROS) accumulation was determined by the DCF fluorescence. Finally, we analyzed RNA‐seq data from human postmortem hippocampi within The Aging, Dementia and Traumatic Brain Injury Study to determine potential correlations between FNDC5 gene expression and AD pathology.ResultWe found that irisin stimulates extracellular BDNF accumulation, ERK 1/2 phosphorylation (i.e. activation) and prevents AβOs‐induced ROS accumulation in primary hippocampal neurons. Analysis of RNA‐seq data indicates that hippocampal FNDC5 gene expression is reduced with aging and tau (assessed by Braak neuropathological scale and hippocampal phospho‐tau immunoreactivity), but not with amyloid pathology in humans.ConclusionThese results indicate potential mechanisms by which FNDC5/irisin signaling promotes neuroprotection and support the notion that stimulation of irisin signaling may be beneficial against neurodegeneration in AD.