Tail-vein injection of MSC-derived small extracellular vesicles facilitates the restoration of hippocampal neuronal morphology and function in APP / PS1 mice

Han Wang,Huiming Li,Yuqi Liu,Yue Hei,Junchen Li,Weiping Liu,Qianfa Long,Xue Wang,Ruijing Zhao,Lina Wang,Tian Wang

doi:10.1038/s41420-021-00620-y

Abstract

Mesenchymal stem-cell-derived small extracellular vesicles (MSC-EVs), as a therapeutic agent, have shown great promise in the treatment of neurological diseases. To date, the neurorestorative effects and underlying mechanism of MSC-EVs in Alzheimer’s disease (AD) are not well known. Herein, we aimed to investigate the action of MSC-EVs on the neuronal deficits in β-amyloid protein (Aβ)-stimulated hippocampal neurons, or AD cell (SHSY5Y cell lines) and animal (APPswe / PS1dE9 mice) models. In the present study, the cell and AD models received a single-dose of MSC-EVs, and were then assessed for behavioral deficits, pathological changes, intracellular calcium transients, neuronal morphology alterations, or electrophysiological variations. Additionally, the nuclear factor E2-related factor 2 (Nrf2, a key mediator of neuronal injury in AD) signaling pathway was probed by western blotting in vitro and in vivo models of AD. Our results showed that MSC-EVs therapy improved the cognitive impairments and reduced the hippocampal Aβ aggregation and neuronal loss in AD mice. Markedly, EV treatment restored the calcium oscillations, dendritic spine alterations, action potential abnormalities, or mitochondrial changes in the hippocampus of AD models. Also, we found that the Nrf2 signaling pathway participated in the actions of MSC-EVs in the cell and animal models. Together, these data indicate that MS-EVs as promising nanotherapeutics for restoration of hippocampal neuronal morphology and function in APP / PS1 mice, further highlighting the clinical values of MSC-EVs in the treatment of AD.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive decline in episodic memory as well as deficits in executive functioning, and is recognized by the World Health Organization as a global public health priority [1]
Our results show that Mesenchymal stem-cell-derived small extracellular vesicles (MSC-extracellular vesicles (EVs)) treatment inhibits the deposition of Aβ protein and neuronal loss observed in the hippocampus of AD mice as well as ameliorates the deficits in neuronal structure and function typified by the calcium transients, morphology alterations, mitochondrial changes, excitability abnormalities, and associated cognitive repairments observed in Aβ-stimulated primary culture or APP / PS1 mice
The present data demonstrated that the Nrf2 signaling pathway participates in the actions of mesenchymal stem cells (MSCs)-EVs on neuronal damage in AD using cell and animal models

Summary

INTRODUCTION

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive decline in episodic memory as well as deficits in executive functioning, and is recognized by the World Health Organization as a global public health priority [1]. Animals in AD + EVs group showed an increased nanotherapeutics to restore hippocampal structure and function discrimination index compared to the AD + saline group Together, these results indicate that MSC-EVs ameliorated Aβ aggregation, neuronal loss, and the cognitive treatment improves the cognitive deficits observed in APP / PS1 deficits in AD mice, further repaired dendritic spine morphology, mice. Our results demonstrate Calcium imbalance induced by amyloid Aβ drives the synaptic the novel therapeutic effects of MSC-EVs in AD and shed light on plasticity and neuronal loss observed in AD [19], we the mechanism underlying its efficacy. As it’s shown in Fig. 4A, calcium imaging revealed differences in the fluorescence proper-

RESULTS

Wang et al 3

DISCUSSION

Findings

ETHICS STATEMENT