WITHDRAWN: Amelioration of hippocampal neuronal morphology and function by mesenchymal stem cell-derived exosomes in APP/PS1 transgenic mice

Abstract Mesenchymal stem cell-derived exosomes (MSC-EXO), as a therapeutic agent, have shown great promise in the treatment of neurological diseases. To date, the therapeutic effects and underlying mechanism(s) of MSC-EXO in Alzheimer's disease (AD) are not well understood. The aim of this study was to investigate the action of MSC-EXO on hippocampal neuronal structure and function in APPswe/PS1dE9 (APP/PS1) transgenic mice. Here, the APP/PS1 transgenic mice received a single-dose of MSC-EXO via a tail vein injection, and were then assessed for pathological changes, neuronal morphology alterations, electrophysiological variations, and behavioral deficits. Additionally, the nuclear factor E2-related factor 2 (Nrf2, a key mediator of oxidative injury) signaling pathway was probed by Western blotting in H2O2-stimulated hippocampal neurons and a mouse model of AD. Our results showed that MSC-EXO therapy inhibited β-amyloid protein (Aβ) aggregation by reducing protein expression of 6E10 (marker of deposited amyloid plaques), repaired the synapses and dendritic spines of hippocampal neurons, restored action potentials in hippocampal pyramidal cells, improved cognitive abilities, and reduced memory impairments in a mouse model of AD. Additionally, we found that the Nrf2 signaling pathway participated in the actions of MSC-EXO, both in vitro and in vivo. Together, these data indicate that MSC-derived exosomes ameliorate the deficits in hippocampal neuronal structure and function associated with the Nrf2 signaling pathway in APP/PS1 transgenic mice, suggesting the MSC-EXO as a functional therapeutic agent in AD.