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

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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.

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References

  1. Doody RS, Farlow M, Aisen PS, Alzheimer’s Disease Cooperative Study Data A, Publication C (2014) Phase 3 trials of solanezumab and bapineuzumab for Alzheimer’s disease. N Engl J Med 370(15):1460–1460. https://doi.org/10.1056/NEJMc1402193

    Article  PubMed  Google Scholar 

  2. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R et al (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):311–321. https://doi.org/10.1056/NEJMoa1312889

    Article  CAS  PubMed  Google Scholar 

  3. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N et al (2018) Trial of Solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378(4):321–330. https://doi.org/10.1056/NEJMoa1705971

    Article  CAS  PubMed  Google Scholar 

  4. Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S et al (2016) The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537(7618):50–56. https://doi.org/10.1038/nature19323

    Article  CAS  PubMed  Google Scholar 

  5. Graham WV, Bonito-Oliva A, Sakmar TP (2017) Update on Alzheimer’s disease therapy and prevention strategies. Annu Rev Med 68:413–430. https://doi.org/10.1146/annurev-med-042915-103753

    Article  CAS  PubMed  Google Scholar 

  6. Ye L, Rasmussen J, Kaeser SA, Marzesco AM, Obermuller U, Mahler J, Schelle J, Odenthal J et al (2017) Abeta seeding potency peaks in the early stages of cerebral beta-amyloidosis. EMBO Rep 18(9):1536–1544. https://doi.org/10.15252/embr.201744067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guerriero F, Sgarlata C, Francis M, Maurizi N, Faragli A, Perna S, Rondanelli M, Rollone M et al (2016) Neuroinflammation, immune system and Alzheimer disease: searching for the missing link. Aging Clin Exp Res 29:821–831. https://doi.org/10.1007/s40520-016-0637-z

    Article  PubMed  Google Scholar 

  8. Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, Zahoor H, Saeed D et al (2017) Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci 11:216. https://doi.org/10.3389/fncel.2017.00216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783. https://doi.org/10.1126/science.aag2590

    Article  CAS  PubMed  Google Scholar 

  10. Di Benedetto S, Muller L, Wenger E, Duzel S, Pawelec G (2017) Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehav Rev 75:114–128. https://doi.org/10.1016/j.neubiorev.2017.01.044

    Article  PubMed  Google Scholar 

  11. Bronzuoli MR, Iacomino A, Steardo L, Scuderi C (2016) Targeting neuroinflammation in Alzheimer’s disease. J Inflamm Res 9:199–208. https://doi.org/10.2147/JIR.S86958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17(1):49–59. https://doi.org/10.1038/nri.2016.123

    Article  CAS  PubMed  Google Scholar 

  13. Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468. https://doi.org/10.1146/annurev-immunol-051116-052358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cornejo F, von Bernhardi R (2016) Age-dependent changes in the activation and regulation of microglia. Adv Exp Med Biol 949:205–226. https://doi.org/10.1007/978-3-319-40764-7_10

    Article  CAS  PubMed  Google Scholar 

  15. Crotti A, Ransohoff RM (2016) Microglial physiology and pathophysiology: insights from genome-wide transcriptional profiling. Immunity 44(3):505–515. https://doi.org/10.1016/j.immuni.2016.02.013

    Article  CAS  PubMed  Google Scholar 

  16. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(7):1276–1290 e1217. https://doi.org/10.1016/j.cell.2017.05.018

    Article  CAS  PubMed  Google Scholar 

  17. Ahmed ME, Iyer S, Thangavel R, Kempuraj D, Selvakumar GP, Raikwar SP, Zaheer S, Zaheer A (2017) Co-localization of glia maturation factor with NLRP3 inflammasome and autophagosome markers in human Alzheimer’s disease brain. J Alzheimers Dis 60(3):1143–1160. https://doi.org/10.3233/JAD-170634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaplan R, Zaheer A, Jaye M, Lim R (1991) Molecular cloning and expression of biologically active human glia maturation factor-beta. J Neurochem 57(2):483–490

    Article  CAS  PubMed  Google Scholar 

  19. Lim R, Miller JF, Zaheer A (1989) Purification and characterization of glia maturation factor beta: a growth regulator for neurons and glia. Proc Natl Acad Sci U S A 86(10):3901–3905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lim R, Zaheer A (1991) Structure and function of glia maturation factor beta. Adv Exp Med Biol 296:161–164

    Article  CAS  PubMed  Google Scholar 

  21. Lim R, Zaheer A, Lane WS (1990) Complete amino acid sequence of bovine glia maturation factor beta. Proc Natl Acad Sci U S A 87(14):5233–5237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stolmeier D, Thangavel R, Anantharam P, Khan MM, Kempuraj D, Zaheer A (2013) Glia maturation factor expression in hippocampus of human Alzheimer’s disease. Neurochem Res 38(8):1580–1589. https://doi.org/10.1007/s11064-013-1059-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Thangavel R, Kempuraj D, Stolmeier D, Anantharam P, Khan M, Zaheer A (2013) Glia maturation factor expression in entorhinal cortex of Alzheimer’s disease brain. Neurochem Res 38(9):1777–1784. https://doi.org/10.1007/s11064-013-1080-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thangavel R, Kempuraj D, Zaheer S, Raikwar S, Ahmed ME, Selvakumar GP, Iyer SS, Zaheer A (2017) Glia maturation factor and mitochondrial uncoupling proteins 2 and 4 expression in the temporal cortex of Alzheimer’s disease brain. Front Aging Neurosci 9:150. https://doi.org/10.3389/fnagi.2017.00150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thangavel R, Stolmeier D, Yang X, Anantharam P, Zaheer A (2012) Expression of glia maturation factor in neuropathological lesions of Alzheimer’s disease. Neuropathol Appl Neurobiol 38(6):572–581. https://doi.org/10.1111/j.1365-2990.2011.01232.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zaheer A, Zaheer S, Thangavel R, Wu Y, Sahu SK, Yang B (2008) Glia maturation factor modulates beta-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage. Brain Res 1208:192–203. https://doi.org/10.1016/j.brainres.2008.02.093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zaheer S, Thangavel R, Sahu SK, Zaheer A (2011) Augmented expression of glia maturation factor in Alzheimer’s disease. Neuroscience 194:227–233. https://doi.org/10.1016/j.neuroscience.2011.07.069

    Article  CAS  PubMed  Google Scholar 

  28. Zaheer S, Thangavel R, Wu Y, Khan MM, Kempuraj D, Zaheer A (2013) Enhanced expression of glia maturation factor correlates with glial activation in the brain of triple transgenic Alzheimer’s disease mice. Neurochem Res 38(1):218–225. https://doi.org/10.1007/s11064-012-0913-z

    Article  CAS  PubMed  Google Scholar 

  29. Khan MM, Zaheer S, Nehman J, Zaheer A (2014) Suppression of glia maturation factor expression prevents 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of mesencephalic dopaminergic neurons. Neuroscience 277:196–205. https://doi.org/10.1016/j.neuroscience.2014.07.003

    Article  CAS  PubMed  Google Scholar 

  30. Selvakumar GP, Iyer SS, Kempuraj D, Raju M, Thangavel R, Saeed D, Ahmed ME, Zahoor H et al (2018) Glia maturation factor dependent inhibition of mitochondrial PGC-1alpha triggers oxidative stress-mediated apoptosis in N27 rat dopaminergic neuronal cells. Mol Neurobiol. https://doi.org/10.1007/s12035-018-0882-6

  31. Callif BL, Maunze B, Krueger NL, Simpson MT, Blackmore MG (2017) The application of CRISPR technology to high content screening in primary neurons. Mol Cell Neurosci 80:170–179. https://doi.org/10.1016/j.mcn.2017.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cyranoski D (2016) CRISPR gene-editing tested in a person for the first time. Nature 539(7630):479. https://doi.org/10.1038/nature.2016.20988

    Article  CAS  PubMed  Google Scholar 

  33. Ledford H (2017) CRISPR fixes disease gene in viable human embryos. Nature 548(7665):13–14. https://doi.org/10.1038/nature.2017.22382

    Article  CAS  PubMed  Google Scholar 

  34. Mandal PK, Ferreira LM, Collins R, Meissner TB, Boutwell CL, Friesen M, Vrbanac V, Garrison BS et al (2014) Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell Stem Cell 15(5):643–652. https://doi.org/10.1016/j.stem.2014.10.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, Madhavan S, Pan X et al (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351(6271):403–407. https://doi.org/10.1126/science.aad5143

    Article  CAS  PubMed  Google Scholar 

  36. Park CY, Kim DH, Son JS, Sung JJ, Lee J, Bae S, Kim JH, Kim DW et al (2015) Functional correction of large factor VIII gene chromosomal inversions in hemophilia a patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell 17(2):213–220. https://doi.org/10.1016/j.stem.2015.07.001

    Article  CAS  PubMed  Google Scholar 

  37. Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O et al (2015) In vivo genome editing using Staphylococcus aureus Cas9. Nature 520(7546):186–191. https://doi.org/10.1038/nature14299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S et al (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13(6):653–658. https://doi.org/10.1016/j.stem.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  39. Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI, Goldmann J, Myers RH et al (2016) Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature 533(7601):95–99. https://doi.org/10.1038/nature17939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Staahl BT, Benekareddy M, Coulon-Bainier C, Banfal AA, Floor SN, Sabo JK, Urnes C, Munares GA et al (2017) Efficient genome editing in the mouse brain by local delivery of engineered Cas9 ribonucleoprotein complexes. Nat Biotechnol 35(5):431–434. https://doi.org/10.1038/nbt.3806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tabebordbar M, Zhu K, Cheng JKW, Chew WL, Widrick JJ, Yan WX, Maesner C, Wu EY et al (2016) In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351(6271):407–411. https://doi.org/10.1126/science.aad5177

    Article  CAS  PubMed  Google Scholar 

  42. Traxler EA, Yao Y, Wang YD, Woodard KJ, Kurita R, Nakamura Y, Hughes JR, Hardison RC et al (2016) A genome-editing strategy to treat beta-hemoglobinopathies that recapitulates a mutation associated with a benign genetic condition. Nat Med 22(9):987–990. https://doi.org/10.1038/nm.4170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang Y, Wang L, Bell P, McMenamin D, He Z, White J, Yu H, Xu C et al (2016) A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol 34(3):334–338. https://doi.org/10.1038/nbt.3469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yin H, Song CQ, Dorkin JR, Zhu LJ, Li Y, Wu Q, Park A, Yang J et al (2016) Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol 34(3):328–333. https://doi.org/10.1038/nbt.3471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, Karumbayaram S, Kumagai-Cresse C et al (2016) A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell 18(4):533–540. https://doi.org/10.1016/j.stem.2016.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zuckermann M, Hovestadt V, Knobbe-Thomsen CB, Zapatka M, Northcott PA, Schramm K, Belic J, Jones DT et al (2015) Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nat Commun 6:7391. https://doi.org/10.1038/ncomms8391

    Article  CAS  PubMed  Google Scholar 

  47. Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27(2–3):229–237

    Article  CAS  PubMed  Google Scholar 

  48. Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P, Kettenmann H (1992) An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res 31(4):616–621. https://doi.org/10.1002/jnr.490310405

    Article  CAS  PubMed  Google Scholar 

  49. Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX 26(2):83–94

    Article  PubMed  Google Scholar 

  50. Zaheer A, Yorek MA, Lim R (2001) Effects of glia maturation factor overexpression in primary astrocytes on MAP kinase activation, transcription factor activation, and neurotrophin secretion. Neurochem Res 26(12):1293–1299

    Article  CAS  PubMed  Google Scholar 

  51. Doudna JA, Charpentier E (2014) Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346(6213):1258096. https://doi.org/10.1126/science.1258096

    Article  CAS  PubMed  Google Scholar 

  52. Swiech L, Heidenreich M, Banerjee A, Habib N, Li Y, Trombetta J, Sur M, Zhang F (2015) In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat Biotechnol 33(1):102–106. https://doi.org/10.1038/nbt.3055

    Article  CAS  PubMed  Google Scholar 

  53. Bengtsson NE, Hall JK, Odom GL, Phelps MP, Andrus CR, Hawkins RD, Hauschka SD, Chamberlain JR et al (2017) Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat Commun 8:14454. https://doi.org/10.1038/ncomms14454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Doria M, Ferrara A, Auricchio A (2013) AAV2/8 vectors purified from culture medium with a simple and rapid protocol transduce murine liver, muscle, and retina efficiently. Hum Gene Ther Methods 24(6):392–398. https://doi.org/10.1089/hgtb.2013.155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Vandenberghe LH, Xiao R, Lock M, Lin J, Korn M, Wilson JM (2010) Efficient serotype-dependent release of functional vector into the culture medium during adeno-associated virus manufacturing. Hum Gene Ther 21(10):1251–1257. https://doi.org/10.1089/hum.2010.107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Su W, Kang J, Sopher B, Gillespie J, Aloi MS, Odom GL, Hopkins S, Case A et al (2016) Recombinant adeno-associated viral (rAAV) vectors mediate efficient gene transduction in cultured neonatal and adult microglia. J Neurochem 136(Suppl 1):49–62. https://doi.org/10.1111/jnc.13081

    Article  CAS  PubMed  Google Scholar 

  57. Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, Mulinyawe SB, Bohlen CJ et al (2016) New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A 113(12):E1738–E1746. https://doi.org/10.1073/pnas.1525528113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rosario AM, Cruz PE, Ceballos-Diaz C, Strickland MR, Siemienski Z, Pardo M, Schob KL, Li A et al (2016) Microglia-specific targeting by novel capsid-modified AAV6 vectors. Mol Ther Methods Clin Dev 3:16026. https://doi.org/10.1038/mtm.2016.26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Taschenberger G, Tereshchenko J, Kugler S (2017) A microRNA124 target sequence restores astrocyte specificity of gfaABC1D-driven transgene expression in AAV-mediated gene transfer. Mol Ther Nucleic Acids 8:13–25. https://doi.org/10.1016/j.omtn.2017.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nishiyama J, Mikuni T, Yasuda R (2017) Virus-mediated genome editing via homology-directed repair in mitotic and Postmitotic cells in mammalian brain. Neuron 96(4):755–768 e755. https://doi.org/10.1016/j.neuron.2017.10.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Murlidharan G, Sakamoto K, Rao L, Corriher T, Wang D, Gao G, Sullivan P, Asokan A (2016) CNS-restricted transduction and CRISPR/Cas9-mediated gene deletion with an engineered AAV vector. Mol Ther Nucleic Acids 5(7):e338. https://doi.org/10.1038/mtna.2016.49

    Article  PubMed  PubMed Central  Google Scholar 

  62. Chew WL, Tabebordbar M, Cheng JK, Mali P, Wu EY, Ng AH, Zhu K, Wagers AJ et al (2016) A multifunctional AAV-CRISPR-Cas9 and its host response. Nat Methods 13(10):868–874. https://doi.org/10.1038/nmeth.3993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kichev A, Eede P, Gressens P, Thornton C, Hagberg H (2017) Implicating receptor activator of NF-kappaB (RANK)/RANK ligand signalling in microglial responses to toll-like receptor stimuli. Dev Neurosci 39(1–4):192–206. https://doi.org/10.1159/000464244

    Article  CAS  PubMed  Google Scholar 

  64. Beutner C, Roy K, Linnartz B, Napoli I, Neumann H (2010) Generation of microglial cells from mouse embryonic stem cells. Nat Protoc 5(9):1481–1494. https://doi.org/10.1038/nprot.2010.90

    Article  CAS  PubMed  Google Scholar 

  65. Douvaras P, Sun B, Wang M, Kruglikov I, Lallos G, Zimmer M, Terrenoire C, Zhang B et al (2017) Directed differentiation of human pluripotent stem cells to microglia. Stem Cell Reports 8(6):1516–1524. https://doi.org/10.1016/j.stemcr.2017.04.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, Bakiasi G, Tsai LH et al (2016) Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med 22(11):1358–1367. https://doi.org/10.1038/nm.4189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hensley K, Floyd RA, Zheng NY, Nael R, Robinson KA, Nguyen X, Pye QN, Stewart CA et al (1999) p38 kinase is activated in the Alzheimer’s disease brain. J Neurochem 72(5):2053–2058

    Article  CAS  PubMed  Google Scholar 

  68. Sun A, Liu M, Nguyen XV, Bing G (2003) P38 MAP kinase is activated at early stages in Alzheimer’s disease brain. Exp Neurol 183(2):394–405

    Article  CAS  PubMed  Google Scholar 

  69. Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF (2001) Localization of active forms of C-Jun kinase (JNK) and p38 kinase in Alzheimer’s disease brains at different stages of neurofibrillary degeneration. J Alzheimers Dis 3(1):41–48

    Article  CAS  PubMed  Google Scholar 

  70. Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H, Shimohama S, Perry G et al (2001) Activation of MKK6, an upstream activator of p38, in Alzheimer’s disease. J Neurochem 79(2):311–318

    Article  CAS  PubMed  Google Scholar 

  71. Zaheer A, Lim R (1998) Overexpression of glia maturation factor (GMF) in PC12 pheochromocytoma cells activates p38 MAP kinase, MAPKAP kinase-2, and tyrosine hydroxylase. Biochem Biophys Res Commun 250(2):278–282. https://doi.org/10.1006/bbrc.1998.9301

    Article  CAS  PubMed  Google Scholar 

  72. Zaheer A, Zaheer S, Sahu SK, Knight S, Khosravi H, Mathur SN, Lim R (2007) A novel role of glia maturation factor: Induction of granulocyte-macrophage colony-stimulating factor and pro-inflammatory cytokines. J Neurochem 101(2):364–376. https://doi.org/10.1111/j.1471-4159.2006.04385.x

    Article  CAS  PubMed  Google Scholar 

  73. Lim R, Zaheer A, Kraakevik JA, Darby CJ, Oberley LW (1998) Overexpression of glia maturation factor in C6 cells promotes differentiation and activates superoxide dismutase. Neurochem Res 23(11):1445–1451

    Article  CAS  PubMed  Google Scholar 

  74. Lim R, Zaheer A, Yorek MA, Darby CJ, Oberley LW (2000) Activation of nuclear factor-kappaB in C6 rat glioma cells after transfection with glia maturation factor. J Neurochem 74(2):596–602

    Article  CAS  PubMed  Google Scholar 

  75. Schnoder L, Hao W, Qin Y, Liu S, Tomic I, Liu X, Fassbender K, Liu Y (2016) Deficiency of neuronal p38alpha MAPK attenuates amyloid pathology in Alzheimer disease mouse and cell models through facilitating lysosomal degradation of BACE1. J Biol Chem 291(5):2067–2079. https://doi.org/10.1074/jbc.M115.695916

    Article  CAS  PubMed  Google Scholar 

  76. McCaskill JL, Ressel S, Alber A, Redford J, Power UF, Schwarze J, Dutia BM, Buck AH (2017) Broad-spectrum inhibition of respiratory virus infection by MicroRNA mimics targeting p38 MAPK signaling. Mol Ther Nucleic Acids 7:256–266. https://doi.org/10.1016/j.omtn.2017.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ji YF, Wang D, Liu YR, Ma XR, Lu H, Zhang BA (2018) MicroRNA-132 attenuates LPS-induced inflammatory injury by targeting TRAF6 in neuronal cell line HT-22. J Cell Biochem. https://doi.org/10.1002/jcb.26720

  78. Hernandez-Rapp J, Rainone S, Goupil C, Dorval V, Smith PY, Saint-Pierre M, Vallee M, Planel E et al (2016) microRNA-132/212 deficiency enhances Abeta production and senile plaque deposition in Alzheimer’s disease triple transgenic mice. Sci Rep 6:30953. https://doi.org/10.1038/srep30953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Salta E, Sierksma A, Vanden Eynden E, De Strooper B (2016) miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer’s brain. EMBO Mol Med 8(9):1005–1018. https://doi.org/10.15252/emmm.201606520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK (2017) Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight 2(7):e91229. https://doi.org/10.1172/jci.insight.91229

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tran DQ, Tse EK, Kim MH, Belsham DD (2016) Diet-induced cellular neuroinflammation in the hypothalamus: mechanistic insights from investigation of neurons and microglia. Mol Cell Endocrinol 438:18–26. https://doi.org/10.1016/j.mce.2016.05.015

    Article  CAS  PubMed  Google Scholar 

  82. Valdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR, Bennett ML, Gerritse I, Fasnacht R et al (2017) Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab 26(1):185–197 e183. https://doi.org/10.1016/j.cmet.2017.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK (2014) Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 9(6):2124–2138. https://doi.org/10.1016/j.celrep.2014.11.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Latta CH, Sudduth TL, Weekman EM, Brothers HM, Abner EL, Popa GJ, Mendenhall MD, Gonzalez-Oregon F et al (2015) Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-beta using BV2 microglial cells and APP/PS1 transgenic mice. J Neuroinflammation 12:41. https://doi.org/10.1186/s12974-015-0243-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.

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  1. Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA

    Sudhanshu P. Raikwar, Ramasamy Thangavel, Iuliia Dubova, Govindhasamy Pushpavathi Selvakumar, Mohammad Ejaz Ahmed, Duraisamy Kempuraj, Smita A. Zaheer, Shankar S. Iyer & Asgar Zaheer

  2. Harry S. Truman Memorial Veteran’s Hospital, US Department of Veterans Affairs, Columbia, MO, USA

    Sudhanshu P. Raikwar, Ramasamy Thangavel, Govindhasamy Pushpavathi Selvakumar, Mohammad Ejaz Ahmed, Duraisamy Kempuraj, Shankar S. Iyer & Asgar Zaheer

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  1. Sudhanshu P. Raikwar
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  2. Ramasamy Thangavel
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Correspondence to Asgar Zaheer.

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Raikwar, S.P., Thangavel, R., Dubova, I. et al. Targeted Gene Editing of Glia Maturation Factor in Microglia: a Novel Alzheimer’s Disease Therapeutic Target. Mol Neurobiol 56, 378–393 (2019). https://doi.org/10.1007/s12035-018-1068-y

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  • DOI: https://doi.org/10.1007/s12035-018-1068-y

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