Abstract
Neurodegeneration in Alzheimer’s disease (AD) results in microglial activation, which may participate in the inflammatory cascade accelerating tissue damage. In this study, we sought to characterize the alleviatory role of microRNA-711 (miR-711) encapsulated in microglia-derived extracellular vesicles (EVs) in a model of AD. Ultracentrifugation was employed to extract EVs from microglia (BV2 cells), which were identified using Western blot analysis of the EVs marker proteins Alix and CD63. A repetitive mild traumatic brain injury (rmTBI) mouse model was induced by controlled cortical impact. After overexpressing miR-711 or 1,4,5-trisphosphate 3-kinase B (Itpkb) in BV2 cells, we evaluated the inflammation in BV2 cells and the ratio of microglia M2/M1. Further, we injected BV2 cell-secreted EVs with overexpressed miR-711 or Itpkb into rmTBI mice through a tail vein to investigate the inflammation markers in mouse serum and, the M2/M1 phenotype ratio of microglia in brain tissues, and to evaluate neurological deficit and cognitive function. The EVs obtained by ultracentrifugation were verified by the presence of Alix and CD63 expression. Mechanistic studies suggested that miR-711 targeted and inhibited Itpkb, thereby repressing Tau phosphorylation and increasing the ratio of M2/M1. Furthermore, miR-711-containing EVs reduced the score of neurological deficits and improved cognitive function in rmTBI mice. The administration of microglia-derived EVs loaded with miR-711, which mediated the hyperphosphorylation of Tau protein in the Itpkb pathway, effectively alleviated neurodegenerative changes and cognitive dysfunction in AD.
Highlights
Alzheimer’s disease (AD) is a severe neurodegenerative disease, in which neuroinflammation plays a significant role (Gate et al, 2020)
After transfection of miR711 mimic in BV2 cells, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) was performed to measure miR-711 expression in BV2 cells and extracellular vesicles (EVs) derived from BV2 cells, showing that miR-711 mimic caused an increase in miR711 expression compared to the treatment with negative control (NC) mimic (p < 0.01) (Figures 1C,D)
Microglia are the resident macrophages in brain, which participate in the neuroinflammatory pathways contributing to neurodegenerative alterations and cognitive dysfunction in AD (Crehan et al, 2012)
Summary
Alzheimer’s disease (AD) is a severe neurodegenerative disease, in which neuroinflammation plays a significant role (Gate et al, 2020). The molecular pathways underlying the pathogenesis of AD remains uncharacterized, there is considerable evidence that activation of microglia is a factor in the neuroinflammation and degeneration of neurons in the context of AD and other neurological disorders (Rothhammer et al, 2018). In the central nervous system, extracellular vesicles (EVs) are critically important for the intercellular communication between neurons and microglia (Surgucheva et al, 2012; Paolicelli et al, 2019). EVs secreted by microglia have been unveiled to participate in the functioning of inflammatory pathways (Yang et al, 2018), in their capacity as mediators of cellular communication by shuttling microRNAs (miRNAs), proteins, and messenger RNAs (mRNAs) (Tesovnik et al, 2020)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
