An enriched environment improves cognitive impairment in an Alzheimer’s disease model by enhancing the secretion of exosomal miR‐146a from the choroid plexus

Abstract

AbstractBackgroundAn enriched environment (EE) is reported to prevent the cognitive impairment and ameliorate the pathologic changes in mouse models of Alzheimer's disease (AD), however the mechanisms have not been fully clarified. In this study, we examined whether an EE enhance the secretion of exosomal miRNA(miR)‐146a from the choroid plexus (CP) and ameliorate the pathologic changes in AD model.MethodMale 5×FAD mice (B6.Cg‐Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax) which develop Aβ plaques in the brain and exhibit cognitive decline were used. At 3 months of age, these mice were divided into control cage (CC) or EE, then housed in either cage until 6 months old. Then, cognitive function was evaluated using Morris Water Maze (MWM) test and mice were sacrificed. In vitro experiments, the secretion of exosomal miR‐146a from CP epithelial cells were evaluated after stimulating of interferon (IFN)‐γ. In addition, we cultured hippocampal astrocytes and added 1 µM Aβ fibrils and 250 ng/ml lipopolysaccharide (LPS) to them to mimic the pathological change of astrocytes in AD. Then we transfected miR‐146a into Aβ/LPS induced inflammatory astrocytes to evaluate the effect of miR‐146aResultIn MWM test, the cognitive impairment in 5×FAD mice was completely prevented by EE. In morphological study, EE ameliorated the expression of TNFα in astrocytes and increased the intensity of synaptophysin in the subiculum area of the hippocampus. In AD model mice treated with EE, increased levels of micro RNA (miR)‐146a and down‐regulation of NF‐κB were observed in the hippocampus. In addition, increased levels of IFN‐γ were seen in serum from mice exposed to an EE. In vitro, enhanced miR‐146a expression was observed in exosomes derived from the CP after IFN‐γ treatment. In further in vitro experiments, miR‐146a transfection ameliorated Aβ/LPS induced astrocytic inflammation by down‐regulating tumor necrosis factor receptor‐associated factor 6 and NF‐κB.ConclusionThe secretion of exosomal miR‐146a from CP, that is enhanced by EE, is a key factor in ameliorating astrocytic inflammation, leading to synaptogenesis and correction of cognitive impairment.