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Prestimulation of Microglia Through TLR4 Pathway Promotes Interferon Beta Expression in a Rat Model of Alzheimer’s Disease

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Abstract

Soluble amyloid beta (Aβ) oligomers are the most common forms of Aβ in the early stage of Alzheimer’s disease (AD). They are highly toxic to the neurons but their capability to activate microglia remains controversial. Microglia develop two distinct phenotypes, classic (M1) and alternative (M2). Tuning of microglia to the alternative (anti-inflammatory) state is of major interest in treatment of neuroinflammatory disease. This study aimed to assess tuning the microglia to produce interferon beta (IFN-β) as an anti-inflammatory cytokine through TLR4 pathway in a rat model of AD. Microglial BV-2 cells were treated with 1 μg/ml lipopolysaccharides (LPS), Monophosphoryl lipid A (MPL), or vehicles for 24 h, and then incubated with Aβ oligomer. After 24 h, cell pellets were harvested and TIR-domain-containing adapter-inducing interferon-β (TRIF), interferon regulatory factor 3 (IRF3), and IFN-β levels were measured. The ligands/vehicle were microinjected into the right ventricle of male Wistar rats every 3 days. Two weeks later, an osmotic pump filled with oligomeric Aβ/vehicle was implanted in the left ventricle. After 2 weeks, TRIF, IRF3, and IFN-β levels were measured in the hippocampal tissue. TNF-α and IFN-β levels were assessed in the hippocampus using immunohistochemistry. The oligomeric Aβ did not change TRIF, IRF3, and IFN-β levels in both cell culture and hippocampal tissue. However, pretreatment with LPS or MPL increased the level of these proteins. BV-2 cells morphologically express M1 state in presence of higher dose of Aβ oligomer (10 μM). Pretreatment with LPS or MPL decreased the TNF-α and increased the number of IFN-β positive cells in the hippocampus of Aβ-treated rats. In conclusion, pretreatment with low dose TLR4 agonists could induce microglia to produce neuroprotective cytokines including IFN-β which may be considered as a potential strategy to combat neuronal degeneration in AD.

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References

  • Aloisi F (2001) Immune function of microglia. Glia 36:165–179

    Article  CAS  PubMed  Google Scholar 

  • Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010) Toll-like receptor 4 in CNS pathologies. J Neurochem 114:13–27

    CAS  PubMed  PubMed Central  Google Scholar 

  • Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M (2005) Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-γ and IL-4 render them protective. Mol Cell Neurosci 29:381–393

    Article  CAS  PubMed  Google Scholar 

  • Chen GY, Nuñez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colton CA, Wilcock DM (2010) Assessing activation states in microglia. CNS Neurol Disord Drug Targets 9:174–191

    Article  CAS  PubMed  Google Scholar 

  • Dementia-statistics (2018) Dementia statistics Alzheimer’s Disease International https://www.alz.co.uk/research/statistics. Accessed 16 May 2017

  • Dirnagl U, Becker K, Meisel A (2009) Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol 8:398–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dmowska M, Cybulska R, Schoenborn R, Piersiak T, Jaworska-Adamu J, Gawron A (2010) Behavioural and histological effects of preconditioning with lipopolysaccharide in epileptic rats. Neurochem Res 35:262–272

    Article  CAS  PubMed  Google Scholar 

  • Doyle SE, Vaidya SA, O'Connell R, Dadgostar H, Dempsey PW, Wu TT, Rao G, Sun R, Haberland ME, Modlin RL, Cheng G (2002) IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17:251–263

    Article  CAS  PubMed  Google Scholar 

  • Elliott GT (1998) Monophosphoryl lipid A induces delayed preconditioning against cardiac ischemia-reperfusion injury. J Mol Cell Cardiol 30:3–17

    Article  CAS  PubMed  Google Scholar 

  • Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido T, Hsiao K, Cole GM (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152:307

    CAS  PubMed  PubMed Central  Google Scholar 

  • Georganopoulou DG, Chang L, Nam J-M, Thaxton CS, Mufson EJ, Klein WL, Mirkin CA (2005) Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc Natl Acad Sci 102:2273–2276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grandvaux N, Servant MJ, Sen GC, Balachandran S, Barber GN, Lin R, Hiscott J (2002) Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J Virol 76:5532–5539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimaldi LME, Zappalà G, Iemolo F, Castellano AE, Ruggieri S, Bruno G, Paolillo A (2014) A pilot study on the use of interferon beta-1a in early Alzheimer’s disease subjects. J Neuroinflammation 11:30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gurley C, Nichols J, Liu S, Phulwani NK, Esen N, Kielian T (2008) Microglia and astrocyte activation by toll-like receptor ligands: modulation by PPAR-agonists. PPAR Res 2008:1–15

  • Heneka MT, Carson MJ, El Khoury J et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hesam S, Khoshkholgh-Sima B, Pourbadie HG, Babapour V, Zendedel M, Sayyah M (2018) Monophosphoryl lipid A and Pam3Cys prevent the increase in seizure susceptibility and epileptogenesis in rats undergoing traumatic brain injury. Neurochem Res 43:1978–1985

    Article  CAS  PubMed  Google Scholar 

  • Hosseini SM, Pourbadie HG, Sayyah M, Zibaii MI, Naderi N (2018) Neuroprotective effect of monophosphoryl lipid A, a detoxified lipid A derivative, in photothrombotic model of unilateral selective hippocampal ischemia in rat. Behav Brain Res 347:26–36

    Article  CAS  PubMed  Google Scholar 

  • Hu F, Ku MC, Markovic D, a Dzaye OD, Lehnardt S, Synowitz M, Wolf SA, Kettenmann H (2014) Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. Int J Cancer 135:2569–2578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobsen JS, Wu C-C, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci 103:5161–5166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janssen B, Vugts DJ, Funke U, Molenaar GT, Kruijer PS, van Berckel BNM, Lammertsma AA, Windhorst AD (2016) Imaging of neuroinflammation in Alzheimer’s disease, multiple sclerosis and stroke: recent developments in positron emission tomography. Biochim Biophys Acta 1862:425–441

    Article  CAS  PubMed  Google Scholar 

  • Kamigaki M, Hide I, Yanase Y, Shiraki H, Harada K, Tanaka Y, Seki T, Shirafuji T, Tanaka S, Hide M, Sakai N (2016) The Toll-like receptor 4-activated neuroprotective microglia subpopulation survives via granulocyte macrophage colony-stimulating factor and JAK2/STAT5 signaling. Neurochem Int 93:82–94

    Article  CAS  PubMed  Google Scholar 

  • Kochan T, Singla A, Tosi J, Kumar A (2012) Toll-like receptor 2 ligand pretreatment attenuates retinal microglial inflammatory response but enhances phagocytic activity toward Staphylococcus aureus. Infect Immun 80:2076–2088

  • Ledeboer A, Brevé JJ, Poole S, Tilders FJ, Van Dam AM (2000) Interleukin-10, interleukin-4, and transforming growth factor-β differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia 30:134–142

    Article  CAS  PubMed  Google Scholar 

  • Lin R, Heylbroeck C, Pitha PM, Hiscott J (1998) Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol Cell Biol 18:2986–2996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marsh B, Stevens SL, Packard AE et al (2009) Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci 29:9839–9849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miwa M, Tsuboi M, Noguchi Y, Enokishima A, Nabeshima T, Hiramatsu M (2011) Effects of betaine on lipopolysaccharide-induced memory impairment in mice and the involvement of GABA transporter 2. J Neuroinflammation 8:153

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murpy M, LeVine H III (2010) Alzheimer’s disease and the β-amyloid peptide. J Alzheimers Dis 19:311–323

    Article  CAS  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  CAS  PubMed  Google Scholar 

  • O'neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13:453–460

    Article  CAS  PubMed  Google Scholar 

  • Paranjape GS, Gouwens LK, Osborn DC, Nichols MR (2012) Isolated amyloid-β (1–42) protofibrils, but not isolated fibrils, are robust stimulators of microglia. ACS Chem Neurosci 3:302–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park K, Lee D, Joe E, Kim S, Jin B (2005) Neuroprotective role of microglia expressing interleukin-4. J Neurosci Res 81:397–402

    Article  CAS  PubMed  Google Scholar 

  • Pourbadie HG, Sayyah M, Khoshkholgh-Sima B, Choopani S, Nategh M, Motamedi F, Shokrgozar MA (2018) Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer’s disease–related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence. Neurobiol Aging 70:203–216

    Article  CAS  PubMed  Google Scholar 

  • Redwine JM, Kosofsky B, Jacobs RE, Games D, Reilly JF, Morrison JH, Young WG, Bloom FE (2003) Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: a magnetic resonance microscopy and stereologic analysis. Proc Natl Acad Sci U S A 100:1381–1386. https://doi.org/10.1073/pnas.242746599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rego Â, Viana SD, Ribeiro CAF, Rodrigues-Santos P, Pereira FC (2016) Monophosphoryl lipid-A: a promising tool for Alzheimer’s disease toll. J Alzheimers Dis 52:1189–1202

    Article  CAS  PubMed  Google Scholar 

  • Reilly JF, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE (2003) Amyloid deposition in the hippocampus and entorhinal cortex: quantitative analysis of a transgenic mouse model. Proc Natl Acad Sci U S A 100:4837–4842. https://doi.org/10.1073/pnas.0330745100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenzweig HL, Minami M, Lessov NS, Coste SC, Stevens SL, Henshall DC, Meller R, Simon RP, Stenzel-Poore MP (2007) Endotoxin preconditioning protects against the cytotoxic effects of TNFα after stroke: a novel role for TNFα in LPS-ischemic tolerance. J Cereb Blood Flow Metab 27:1663–1674

    Article  CAS  PubMed  Google Scholar 

  • Sisodia SS, Price D (1995) Role of the beta-amyloid protein in Alzheimer’s disease. FASEB J 9:366–370

    Article  CAS  PubMed  Google Scholar 

  • Sondag CM, Dhawan G, Combs CK (2009) Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflammation 6:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suh H-S, Zhao M-L, Choi N, Belbin TJ, Brosnan CF, Lee SC (2009) TLR3 and TLR4 are innate antiviral immune receptors in human microglia: role of IRF3 in modulating antiviral and inflammatory response in the CNS. Virology 392:246–259

    Article  CAS  PubMed  Google Scholar 

  • Tahara K, Kim H-D, Jin J-J, Maxwell JA, Li L, Fukuchi K-i (2006) Role of toll-like receptor signalling in Aβ uptake and clearance. Brain 129:3006–3019

    Article  PubMed  Google Scholar 

  • Tarassishin L, Suh H-S, Lee SC (2011) Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. J Neuroinflammation 8:187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thaney VE, O’Neill AM, Hoefer MM, Maung R, Sanchez AB, Kaul M (2017) IFNβ protects neurons from damage in a murine model of HIV-1 associated brain injury. Sci Rep 7:46514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Toyoda T, Kassell NF, Lee KS (2000) Induction of tolerance against ischemia/reperfusion injury in the rat brain by preconditioning with the endotoxin analog diphosphoryl lipid a. J Neurosurg 92:435–441

    Article  CAS  PubMed  Google Scholar 

  • Vartanian KB, Stevens SL, Marsh BJ, Williams-Karnesky R, Lessov NS, Stenzel-Poore MP (2011) LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury. J Neuroinflammation 8:140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539. https://doi.org/10.1038/416535a

    Article  CAS  PubMed  Google Scholar 

  • White JA, Manelli AM, Holmberg KH, Van Eldik LJ, LaDu MJ (2005) Differential effects of oligomeric and fibrillar amyloid-β1–42 on astrocyte-mediated inflammation. Neurobiol Dis 18:459–465

    Article  CAS  PubMed  Google Scholar 

  • Wood H (2017) Alzheimer disease: twin peaks of microglial activation observed in Alzheimer disease. Nat Rev Neurol 13:129

    PubMed  Google Scholar 

  • Yao Y, Li J, Niu Y et al (2015) Resveratrol inhibits oligomeric Aβ-induced microglial activation via NADPH oxidase. Mol Med Rep 12:6133–6139

    Article  CAS  PubMed  Google Scholar 

  • Yu JT, Lee CH, Yoo K-Y, Choi JH, Li H, Park OK, Yan B, Hwang IK, Kwon YG, Kim YM, Won MH (2010) Maintenance of anti-inflammatory cytokines and reduction of glial activation in the ischemic hippocampal CA1 region preconditioned with lipopolysaccharide. J Neurol Sci 296:69–78

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Xie W, Xiao Q, Beers DR, Appel SH (2006) Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 99:1176–1187

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Spittau B, Krieglstein K (2012) TGFβ signalling plays an important role in IL4-induced alternative activation of microglia. J Neuroinflammation 9:210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran

    Niloufar Yousefi, Mohammad Sayyah, Soheil Ghassemi, Shayan Aliakbari & Hamid Gholami Pourbadie

  2. Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Niloufar Yousefi, Fattah Sotoodehnejadnematalahi & Nooshin Heshmati-Fakhr

  3. Department of Pharmacodynamy and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Masoud Hoseini

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  1. Niloufar Yousefi
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  2. Fattah Sotoodehnejadnematalahi
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Correspondence to Hamid Gholami Pourbadie.

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Yousefi, N., Sotoodehnejadnematalahi, F., Heshmati-Fakhr, N. et al. Prestimulation of Microglia Through TLR4 Pathway Promotes Interferon Beta Expression in a Rat Model of Alzheimer’s Disease. J Mol Neurosci 67, 495–503 (2019). https://doi.org/10.1007/s12031-018-1249-1

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