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Molecular Neurobiology

, Volume 56, Issue 1, pp 378–393 | Cite as

Targeted Gene Editing of Glia Maturation Factor in Microglia: a Novel Alzheimer’s Disease Therapeutic Target

  • Sudhanshu P. Raikwar
  • Ramasamy Thangavel
  • Iuliia Dubova
  • Govindhasamy Pushpavathi Selvakumar
  • Mohammad Ejaz Ahmed
  • Duraisamy Kempuraj
  • Smita A. Zaheer
  • Shankar S. Iyer
  • Asgar ZaheerEmail author
Article

Abstract

Alzheimer’s disease (AD) is a devastating, progressive neurodegenerative disorder that leads to severe cognitive impairment in elderly patients. Chronic neuroinflammation plays an important role in the AD pathogenesis. Glia maturation factor (GMF), a proinflammatory molecule discovered in our laboratory, is significantly upregulated in various regions of AD brains. We have previously reported that GMF is predominantly expressed in the reactive glial cells surrounding the amyloid plaques (APs) in the mouse and human AD brain. Microglia are the major source of proinflammatory cytokines and chemokines including GMF. Recently clustered regularly interspaced short palindromic repeats (CRISPR) based genome editing has been recognized to study the functions of genes that are implicated in various diseases. Here, we investigated if CRISPR-Cas9-mediated GMF gene editing leads to inhibition of GMF expression and suppression of microglial activation. Confocal microscopy of murine BV2 microglial cell line transduced with an adeno-associated virus (AAV) coexpressing Staphylococcus aureus (Sa) Cas9 and a GMF-specific guide RNA (GMF-sgRNA) revealed few cells expressing SaCas9 while lacking GMF expression, thereby confirming successful GMF gene editing. To further improve GMF gene editing efficiency, we developed lentiviral vectors (LVs) expressing either Streptococcus pyogenes (Sp) Cas9 or GMF-sgRNAs. BV2 cells cotransduced with LVs expressing SpCas9 and GMF-sgRNAs revealed reduced GMF expression and the presence of indels in the exons 2 and 3 of the GMF coding sequence. Lipopolysaccharide (LPS) treatment of GMF-edited cells led to reduced microglial activation as shown by reduced p38 MAPK phosphorylation. We believe that targeted in vivo GMF gene editing has a significant potential for developing a unique and novel AD therapy.

Keywords

Adeno-associated virus Alzheimer’s disease CRISPR-Cas9 Glia maturation factor Lentiviral vectors Microglia 

Notes

Acknowledgements

The authors would like to acknowledge the Veterans Affairs Merit Award I01BX002477 and the National Institutes of Health Grant AG048205 to AZ. The authors would like to thank Prof. Miguel Sena-Esteves, University of Massachusetts, Worcester, for providing the AAV plasmid pGG-B1 and Prof. Didier Trono, Ecole Polytechnique Federale de Lausanne (EPFL) for providing the pMDLg/pRRE, pRSV-Rev, and pMD2.G lentiviral packaging plasmids. The authors are thankful to Dr. Alexander Jurkevich, Associate Director, University of Missouri Molecular Cytology Core for help with confocal microscopy and Mr. Daniel E. Jackson, University of Missouri Cell and Immunobiology Core for help with flow cytometry.

Compliance with Ethical Standards

Conflict of Interest

The authors confirm that they have no conflict of interest.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sudhanshu P. Raikwar
    • 1
    • 2
  • Ramasamy Thangavel
    • 1
    • 2
  • Iuliia Dubova
    • 1
  • Govindhasamy Pushpavathi Selvakumar
    • 1
    • 2
  • Mohammad Ejaz Ahmed
    • 1
    • 2
  • Duraisamy Kempuraj
    • 1
    • 2
  • Smita A. Zaheer
    • 1
  • Shankar S. Iyer
    • 1
    • 2
  • Asgar Zaheer
    • 1
    • 2
    Email author return OK on get
  1. 1.Department of Neurology, Center for Translational Neuroscience, School of MedicineUniversity of MissouriColumbiaUSA
  2. 2.Harry S. Truman Memorial Veteran’s Hospital, US Department of Veterans AffairsColumbiaUSA

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