Research Paper Volume 14, Issue 7 pp 3070—3083

Hypoxic pretreatment of adipose-derived stem cell exosomes improved cognition by delivery of circ-Epc1 and shifting microglial M1/M2 polarization in an Alzheimer’s disease mice model

Haining Liu1,2, *, , Mingming Jin3, *, , Minxiu Ji1,2, , Wei Zhang1,2, , An Liu1,2, , Tao Wang1,2, ,

  • 1 Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
  • 2 Alzheimer’s Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai 200030, China
  • 3 Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
* Equal contribution

Received: October 28, 2021       Accepted: February 24, 2022       Published: April 1, 2022
How to Cite

Copyright: © 2022 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Alzheimer’s disease (AD) is the most common dementia in the world. Increasing evidence has shown that exosomes from hypoxic pretreated adipose-derived stem cells (ADSCs) could be an effective cognitive function therapeutic in AD-associated pathophysiology. However, their role and regulatory mechanism remain largely unknown. High-throughput sequencing was used to identify differentially expressed circRNAs from ADSCs or hypoxia pretreated ADSC exosomes. Luciferase reporter assays and RT-qPCR were used to investigate the relationships between circ-Epc1, miR-770-3p, and TREM2. APP/PS1 double transgenic AD model mice were then used to study therapeutic effects regarding circ-Epc1 in ADSC exosomes. BV2 cells were used to show the regulatory relationships between circ-Epc1, miR-770-3p, and TREM2 and to show how these interactions modulated phenotypic transformations and inflammatory cytokine expressions in microglia. The results showed that exosomes from hypoxia pretreated ADSCs had a good therapeutic effect on improving cognitive functions by decreasing neuronal damage in the hippocampus. High-throughput sequencing showed that circ-Epc1 played an important role in hypoxia-pretreated ADSC exosomes regarding their ability to improve cognitive functions. Luciferase reporter assays showed that TREM2 and miR-770-3p were downstream targets of circ-Epc1. Overexpressing miR-770-3p or downregulating TREM2 reversed the effects of circ-Epc1 on M2 microglia during lipopolysaccharide treatment. In vivo experiments showed that circ-Epc1-containing ADSC exosomes increased the therapeutic effect of exosomes by improving cognitive function, decreasing neuronal damage, and shifting hippocampal microglia from the M1 polarization to the M2 polarization stages. Taken together, the data show that hypoxic pretreatment of ADSC exosomes improved cognition by delivery of circ-Epc1 and by shifting microglial M1/M2 polarization in an AD mouse model.


AD: Alzheimer’s disease; ADSCs: adipose-derived stem cell; circRNAs: circular RNAs; Aβ: β-amyloid; FBS: fetal bovine serum; MSCs: mesenchymal stem cells; PBS: phosphate-buffered saline.