Hypoxic Pretreatment Adipose-derived Stem Cell Exosomes Improve Cognition by Delivery Circ-Epc1 and Shifting Microglial M1/M2 Polarization in Alzheimer’s Disease Mice Model

Abstract

Background: Alzheimer’s disease (AD) is the most major dementia in the globe. Increasing evidence informs that exosomes from hypoxic pretreatment adipose-derived stem cells (ADSCs) could therapeutically affect cognitive function in AD-associated pathophysiology. However, their role and regulatory mechanism remain largely unknown. Methods: High-throughput sequencing was used to identify differentially expressed exosomal circRNAs from ADSCs or hypoxia pretreated ADSCs. 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 utilized to study therapeutic effect regarding circ-Epc1 in ADSCs exosomes. BV2 cells were used to understand the regulatory relationship between circ-Epc1, miR-770-3p, and TREM2 and how these interactions modulated phenotypic transformation and inflammatory cytokine expression in microglia. Results: The result show that exosomes from hypoxia pretreatment ADSCs had a greater therapeutic effect at improving cognitive function by decreasing neuronal damage in the hippocampus. High-throughput sequencing found that circ-Epc1 played an important role in hypoxia pretreated ADSC exosomes regarding their ability to improve cognitive function. 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 under LPS treatment. In vivo experiments showed that circ-Epc1-containing ADSC exosomes increased the therapeutic effect of exosome at improving cognitive function by decreasing neuronal damage and shifting hippocampal microglia from M1 to M2 polarization. Conclusions: Taken together, the data found that hypoxic pretreatment ADSCs exosomes improve cognition by delivery circ-Epc1 and shifting microglial M1/M2 polarization in alzheimer’s disease mice model.