ADMSC Exo‐MicroRNA‐22 improve neurological function and neuroinflammation in mice with Alzheimer's disease

Abstract

The previous study by our group has found that miRNA‐22 can inhibit pyroptosis by targeting GSDMD and improve the memory and motor ability of mice with Alzheimer's disease (AD) mice by inhibiting inflammatory response. In recent years, stem cells and their exosomes have been reported to have good therapeutic effects on AD; therefore, we hypothesize that miRNA‐22 is likely to play a synergistic therapeutic effect. In this study, adipose‐derived mesenchymal stem cells (ADMSCs) were transfected into miRNA‐22 mimic to obtain miRNA‐22 loaded exosomes (Exo‐miRNA‐22), which was further used for the treatment and nerve repair of AD. In brief, 4‐month‐old APP/PS1 mice were assigned into the control group, Exo and Exo‐miRNA‐22 groups. After exosome transplantation, we observed changes in the motor and memory ability of mice. In addition, ELISA was used to detect the expression of inflammatory factors in cerebrospinal fluid and peripheral blood, Nissl staining was used to assess the survival of mouse nerve cells, immunofluorescence staining was used to determine the activation of microglia, and Western blot was utilized to detect the expression of pyroptosis‐related proteins. As a result, the nerve function and motor ability were significantly higher in mice in the Exo‐miRNA‐22 group than those in the control group and Exo group. Meanwhile, the survival level of nerve cells in mice was higher in the Exo‐miRNA‐22 group, and the expression of inflammatory factors was lower than that of the Exo group, indicating Exo‐miRNA‐22 could significantly suppress neuroinflammation. In vitro culture of PC12 cells, Aβ25‐35‐induced cell damage, detection of PC12 apoptotic level, the release of inflammatory factors and the expression of pyroptosis‐related proteins showed that Exo‐miRNA‐22 could inhibit PC12 apoptosis and significantly decrease the release of inflammatory factors. In this study, we found that miRNA‐22‐loaded ADMSC‐derived exosomes could decrease the release of inflammatory factors by inhibiting pyroptosis, thereby playing a synergetic therapeutic role with exosomes on AD, which is of great significance in AD research.

Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects

“…Also, miR-29 enriched MSC-derived exosome therapy resulted in decreased pathological impacts of Aβ peptide in a rodent model of AD and then improved spatial learning and memory [ 143 ]. On the other hand, miRNA-22-loaded AT-MSC-derived exosomes enhanced the motor and memory capability of mice model of AD by improving neural survival in vivo [ 144 ]. In vitro analysis also suggested that improved neural survival relies on the inhibition of inflammatory factors secretion and downregulation of the pyroptosis process, which was provoked by exosomal miRNA-22 [ 144 ].…”

“…On the other hand, miRNA-22-loaded AT-MSC-derived exosomes enhanced the motor and memory capability of mice model of AD by improving neural survival in vivo [ 144 ]. In vitro analysis also suggested that improved neural survival relies on the inhibition of inflammatory factors secretion and downregulation of the pyroptosis process, which was provoked by exosomal miRNA-22 [ 144 ].…”

Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases

“…The miR-125a found in BM-MSCs promotes M2 macrophage polarization, which was attenuated by the knockdown of this miRNA (Chang et al, 2021 ). Transfection of AT-MSCs with miR-22 mimics resulted in a mir-22 enriched pool of Evs and reduced inflammation in a mouse model of AD (Zhai et al, 2021 ). Also, Evs of MSCs transfected with miR-26a-5p and miR-221-3p mimic, respectively, attenuated ischemia/reperfusion injury and stroke (Ai et al, 2021 ; Cheng et al, 2021 ).…”

The Extracellular MicroRNAs on Inflammation: A Literature Review of Rodent Studies

“…In a mouse model of Alzheimer’s disease induced by LPS, miR-146a was enriched in EVs under inflammatory conditions, and EVs can induce inflammation and LPS tolerance [ 79 ]. Using the APP/PS1 mouse model of Alzheimer’s disease, miR-22 in exosomes from ADMSC enhanced neurological function, inhibited PC12 apoptosis, and decreased inflammatory factors by inhibiting proptosis [ 80 ].…”