Intranasal Delivery of lincRNA-Cox2 siRNA Loaded Extracellular Vesicles Decreases Lipopolysaccharide-Induced Microglial
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Intranasal Delivery of lincRNA-Cox2 siRNA Loaded Extracellular Vesicles Decreases Lipopolysaccharide-Induced Microglial Proliferation in Mice Ke Liao 1 & Fang Niu 1 & Raghubendra Singh Dagur 1 & Mengfan He 2 & Changhai Tian 3 & Guoku Hu 1 Received: 28 February 2019 / Accepted: 9 July 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract Long non-coding RNAs (lncRNAs), including long intergenic non-coding RNAs (lincRNAs), play an important regulatory role in controlling various biological processes. Both in vitro and in vivo studies have demonstrated that lincRNA-Cox2 plays a global regulatory role in regulating the expression of immune genes. Extracellular vesicles (EVs) are cell-derived nanosized membrane vesicles that have gained increasing attention in recent years due to their ability to efficiently deliver therapeutics to specific target organs or cell types. In this study, we found that lincRNA-Cox2 controls the expression of a set of cell cycle genes in lipopolysaccharide (LPS)-stimulated microglial cells. Our in vitro study suggested that knocking down lincRNA-Cox2 reversed LPSinduced microglial proliferation. In addition, our in vivo study demonstrated that intranasally delivered lincRNA-Cox2-siRNA loaded EVs could reach the brain resulting in a significant decrease in the expression of lincRNA-Cox2 in the microglia. Importantly, lincRNA-Cox2-siRNA loaded EVs also decreased LPS-induced microglial proliferation in mice. These findings indicate that intranasal delivery of EV-loaded small RNA could be developed as therapeutics for treatment of a multitude of CNS disorders. Keywords lincRNA-Cox2 . Microglial proliferation . Extracellular vesicle . Intranasal delivery . LPS
Introduction Under normal/physiological conditions, the number of microglial cells remains stable in the adult brain throughout life in mice and humans (Askew et al. 2017). However, the number of microglia is dramatically altered in several CNS diseases. For example, the number of microglia is increased by at least 40% in 5xfAD mice (a mouse model of Alzheimer’s disease (AD)) compared to control mice (Spangenberg et al. 2016). Similarly, LPS treatment significantly increases the number of microglia both in vitro and in vivo (Monje et al. 2003). Interestingly, following depletion * Guoku Hu [email protected] 1
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA
2
School of Medicine, Tongji University, Shanghai 200092, China
3
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
of microglial numbers in 5xfAD mice, there was a substantial recovery of contextual memory, and reversal of dendritic spine loss and subsequent neuronal loss (Spangenberg et al. 2016), thereby indicating that targeting microglial proliferation could be a therapeutic strategy for the treatment of neurodegenerative diseases. Long non-coding RNAs (lncRNAs), including long intergenic non-cod
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