Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease

Published:November 20, 2018DOI:https://doi.org/10.1016/j.jneuroim.2018.11.010

      Highlights

      • Activation of microglia is one of the early events of the AD.
      • Modulation of microglia activation in the early stage is the best therapeutic approached to reverse AD progression.
      • Suppressing neuroinflammation by inhibiting activation of NF-kB signalling and P2X7/NLRP 3 pathways.
      • Purinoreceptor (P2X7) antagonist could be an important therapeutic target, especially in a neuroinflammation induced AD in the early stage.

      Abstract

      Microglial activation is a distinguished attribute in many neurodegenerative diseases of aging. Compelling evidence suggests that neuroinflammation stimulated by microglia, the resident macrophage-like immune cells in the brain, play a contributing role in the pathogenesis of Alzheimer's disease (AD). Postmortem brain tissue of individuals with AD has credibly demonstrated that neuroinflammation is likely to be a key driver of the disease. Recently, It has been found that manipulating β-amyloid directly is an impracticable approach for therapeutic intervention due to the failure of β-amyloid-lowering drugs in clinical trials. Further, Current treatments relieve only symptoms and modestly improve disease condition but do not reverse or prevent disease. Therefore, Inhibition of microglia activation is effective strategies against the multifactorial and complex AD. More recently there has been a center of attention on converting microglia from this classic state to an alternate state in which the noxious effects are reduced and their phagocytic action toward Aβ improved. The nuclear factor-kappa B (NF- kB) and NLRP3 inflammasome activation by P2X7/NLRP3/caspase 1 pathways are closely linked to Alzheimer’s disease (AD) via neuroinflammation, therefore it could be a rational strategy to target these proteins to counteract the AD pathology. These strategies could work effectively if therapeutic intervention started at an early stage. This review highlights the potentials of drugs acting on the P2X7 receptor and its downstream protein targets for inhibition of neuroinflammation. Thus it might act as a futuristic strategy to treat Alzheimer’s disease.

      Graphical abstract

      Keyword

      Abbreviations:

      NLRP3 (NOD like receptor protein 3), ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), ATP (adenosine triphosphate), CARD (caspase recruitment domain), DAMPS (danger or damage associated molecular patterns), IL (interleukin), LRR (leucine-rich repeat), NACHT (central nucleotide-binding and oligomerization), NF-κB (nuclear factor kappa B), P2X7 (P2X purinergic receptor 7), PAMPS (pathogen associated molecular patterns), PYD (pyrin domain), TLR (Toll-like receptor), MD2 (Muramyl dipeptide)
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      References

        • Adinolfi E.
        • Giuliani A.L.
        • De Marchi E.
        • Pegoraro A.
        • Orioli E.
        • Di Virgilio F.
        The P2X7 receptor: a main player in inflammation.
        Biochem. Pharmacol. 2018; https://doi.org/10.1016/j.bcp.2017.12.021
        • Agarwal S.
        • Yadav A.
        • Chaturvedi R.K.
        Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders.
        Biochem. Biophys. Res. Commun. 2017; 483: 1166-1177https://doi.org/10.1016/j.bbrc.2016.08.043
        • Aisen P.S.
        • Gauthier S.
        • Ferris S.H.
        • Saumier D.
        • Haine D.
        • Garceau D.
        • Duong A.
        • Suhy J.
        • Oh J.
        • Lau W.C.
        • Sampalis J.
        Tramiprosate in mild-to-moderate Alzheimer’s disease – a randomized, double-blind, placebo-controlled, multi-centre study (the alphase study).
        Arch. Med. Sci. 2011; 7: 102-111https://doi.org/10.5114/aoms.2011.20612
        • Allan S.M.
        • Tyrrell P.J.
        • Rothwell N.J.
        Interleukin-1 and neuronal injury.
        Nat. Rev. Immunol. 2005; 5: 629-640https://doi.org/10.1038/nri1664
        • Alzheimer's Association
        Alzheimer’s disease facts and figures.
        Alzheimers Dement. 2018; 14: 367-429https://doi.org/10.1016/j.jalz.2018.02.001
        • Ameriks M.K.
        • Ao H.
        • Carruthers N.I.
        • Lord B.
        • Ravula S.
        • Rech J.C.
        • Savall B.M.
        • Wall J.L.
        • Wang Q.
        • Bhattacharya A.
        • Letavic M.A.
        Preclinical characterization of substituted 6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one P2X7 receptor antagonists.
        Bioorg. Med. Chem. Lett. 2016; 26: 257-261https://doi.org/10.1016/j.bmcl.2015.12.052
        • An Y.
        • Varma V.R.
        • Varma S.
        • Casanova R.
        • Dammer E.
        • Pletnikova O.
        • Chia C.W.
        • Egan J.M.
        • Ferrucci L.
        • Troncoso J.
        • Levey A.I.
        • Lah J.
        • Seyfried N.T.
        • Legido-Quigley C.
        • O’Brien R.
        • Thambisetty M.
        Evidence for brain glucose dysregulation in Alzheimer’s disease.
        Alzheimers Dement. 2018; 14: 318-329https://doi.org/10.1016/j.jalz.2017.09.011
        • Asatryan L.
        • Ostrovskaya O.
        • Lieu D.
        • Davies D.L.
        Ethanol differentially modulates P2X4 and P2X7 receptor activity and function in BV2 microglial cells.
        Neuropharmacology. 2018; 128: 11-21https://doi.org/10.1016/J.NEUROPHARM.2017.09.030
        • Bartlett R.
        • Stokes L.
        • Sluyter R.
        The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease.
        Pharmacol. Rev. 2014; 66: 638-675https://doi.org/10.1124/pr.113.008003
        • Baudelet D.
        • Lipka E.
        • Millet R.
        • Ghinet A.
        Involvement of the P2X7 purinergic receptor in inflammation: an update of antagonists series since 2009 and their promising therapeutic potential.
        Curr. Med. Chem. 2015; 22: 713-729
        • Beaino W.
        • Janssen B.
        • Kooij G.
        • van der Pol S.M.A.
        • van Het Hof B.
        • van Horssen J.
        • Windhorst A.D.
        • de Vries H.E.
        Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis.
        J. Neuroinflammation. 2017; 14https://doi.org/10.1186/s12974-017-1034-z
        • Bhattacharya A.
        Recent advances in CNS P2X7 physiology and pharmacology: focus on neuropsychiatric disorders.
        Front. Pharmacol. 2018; https://doi.org/10.1053/ejvs.1999.0843
        • Bhattacharya A.
        • Jones D.N.C.
        Emerging role of the P2X7-NLRP3-IL1β pathway in mood disorders.
        Psychoneuroendocrinology. 2018; 98: 95-100https://doi.org/10.1016/j.psyneuen.2018.08.015
        • Boche D.
        • Perry V.H.
        • Nicoll J.A.R.
        Review: activation patterns of microglia and their identification in the human brain.
        Neuropathol. Appl. Neurobiol. 2013; 39: 3-18https://doi.org/10.1111/nan.12011
        • Borzelleca J.F.
        • Olson J.W.
        • Reno F.E.
        Lifetime toxicity/carcinogenicity studies of FD & C Red No. 40 (allura red) in mice.
        Food Chem. Toxicol. 1991; 29: 313-319https://doi.org/10.1016/0278-6915(91)90202-I
        • Brown G.C.
        • Neher J.J.
        Microglial phagocytosis of live neurons.
        Nat. Rev. Neurosci. 2014; 15: 209-216https://doi.org/10.1038/nrn3710
        • Burnstock G.
        Purine and pyrimidine receptors.
        Cell. Mol. Life Sci. 2007; 64: 1471-1483https://doi.org/10.1007/s00018-007-6497-0
        • Burnstock G.
        An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration.
        Neuropharmacology. 2016; 104: 4-17https://doi.org/10.1016/j.neuropharm.2015.05.031
        • Burnstock G.
        • Kennedy C.
        Is there a basis for distinguishing two types of P2-purinoceptor?.
        Gen. Pharmacol. Vasc. Syst. 1985; 16: 433-440https://doi.org/10.1016/0306-3623(85)90001-1
        • Burnstock G.
        • Knight G.E.
        The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression.
        Purinergic Signal. 2018; https://doi.org/10.1007/s11302-017-9593-0
        • Cai Z.
        • Hussain M.D.
        • Yan L.J.
        Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease.
        Int. J. Neurosci. 2014; 124: 307-321https://doi.org/10.3109/00207454.2013.833510
        • Castello M.A.
        • Jeppson J.D.
        • Soriano S.
        Moving beyond anti-amyloid therapy for the prevention and treatment of Alzheimer’s disease.
        BMC Neurol. 2014; 14https://doi.org/10.1186/s12883-014-0169-0
        • Chen X.
        • Hu J.
        • Jiang L.
        • Xu S.
        • Zheng B.
        • Wang C.
        • Zhang J.
        • Wei X.
        • Chang L.
        • Wang Q.
        Brilliant Blue G improves cognition in an animal model of Alzheimer’s disease and inhibits amyloid-β-induced loss of filopodia and dendrite spines in hippocampal neurons.
        Neuroscience. 2014; 279: 94-101https://doi.org/10.1016/j.neuroscience.2014.08.036
        • Chhor V.
        • Le Charpentier T.
        • Lebon S.
        • Oré M.-V.
        • Celador I.L.
        • Josserand J.
        • Degos V.
        • Jacotot E.
        • Hagberg H.
        • Sävman K.
        • Mallard C.
        • Gressens P.
        • Fleiss B.
        Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro.
        Brain Behav. Immun. 2013; 32: 70-85https://doi.org/10.1016/j.bbi.2013.02.005
        • Chrovian C.C.
        • Rech J.C.
        • Bhattacharya A.
        • Letavic M.A.
        P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders.
        Prog. Med. Chem. 2014; 53: 65-100https://doi.org/10.1016/B978-0-444-63380-4.00002-0
        • Chrovian C.C.
        • Soyode-Johnson A.
        • Ao H.
        • Bacani G.M.
        • Carruthers N.I.
        • Lord B.
        • Nguyen L.
        • Rech J.C.
        • Wang Q.
        • Bhattacharya A.
        • Letavic M.A.
        Novel phenyl-substituted 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists with robust target engagement in rat brain.
        ACS Chem. Neurosci. 2016; 7: 490-497https://doi.org/10.1021/acschemneuro.5b00303
        • Chrovian C.C.
        • Soyode-Johnson A.
        • Peterson A.A.
        • Gelin C.F.
        • Deng X.
        • Dvorak C.A.
        • Carruthers N.I.
        • Lord B.
        • Fraser I.
        • Aluisio L.
        • Coe K.J.
        • Scott B.
        • Koudriakova T.
        • Schoetens F.
        • Sepassi K.
        • Gallacher D.J.
        • Bhattacharya A.
        • Letavic M.A.
        A dipolar cycloaddition reaction to access 6-methyl-4,5,6,7-tetrahydro-1 H -[1,2,3]triazolo[4,5- c ]pyridines enables the discovery synthesis and preclinical profiling of a P2X7 antagonist clinical candidate.
        J. Med. Chem. 2018; 61: 207-223https://doi.org/10.1021/acs.jmedchem.7b01279
        • Chrovian C.C.
        • Soyode-Johnson A.
        • Peterson A.A.
        • Gelin C.F.
        • Deng X.
        • Dvorak C.A.
        • Carruthers N.I.
        • Lord B.
        • Fraser I.
        • Aluisio L.
        • Coe K.J.
        • Scott B.
        • Koudriakova T.
        • Schoetens F.
        • Sepassi K.
        • Gallacher D.J.
        • Bhattacharya A.
        • Letavic M.A.
        A dipolar cycloaddition reaction to access 6-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines enables the discovery synthesis and preclinical profiling of a P2X7 antagonist clinical candidate.
        J. Med. Chem. 2018; 61: 207-223https://doi.org/10.1021/acs.jmedchem.7b01279
        • Chuang K.-A.
        • Li M.-H.
        • Lin N.-H.
        • Chang C.-H.
        • Lu I.-H.
        • Pan I.-H.
        • Takahashi T.
        • Perng M.-D.
        • Wen S.-F.
        Rhinacanthin C alleviates amyloid- βfibrils’ toxicity on neurons and attenuates neuroinflammation triggered by LPS, amyloid- β, and interferon- γ in glial cells.
        Oxidative Med. Cell. Longev. 2017; 2017: 1-18https://doi.org/10.1155/2017/5414297
        • Czeh M.
        • Gressens P.
        • Kaindl A.M.
        The Yin and Yang of microglia.
        Dev. Neurosci. 2011; 33: 199-209https://doi.org/10.1159/000328989
        • Dai J.-N.
        • Zong Y.
        • Zhong L.-M.
        • Li Y.-M.
        • Zhang W.
        • Bian L.-G.
        • Ai Q.-L.
        • Liu Y.-D.
        • Sun J.
        • Lu D.
        Gastrodin inhibits expression of inducible NO synthase, cyclooxygenase-2 and proinflammatory cytokines in cultured LPS-stimulated microglia via MAPK pathways.
        PLoS One. 2011; 6e21891https://doi.org/10.1371/journal.pone.0021891
        • Daniels M.J.
        • Rivers-Auty J.
        • Schilling T.
        • Spencer N.G.
        • Watremez W.
        • Fasolino V.
        • Booth S.J.
        • White C.S.
        • Baldwin A.G.
        • Freeman S.
        • Wong R.
        • Latta C.
        • Yu S.
        • Jackson J.
        • Fischer N.
        • Koziel V.
        • Pillot T.
        • Bagnall J.
        • Allan S.M.
        • Paszek P.
        • Galea J.
        • Harte M.K.
        • Eder C.
        • Lawrence C.B.
        • Brough D.
        Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models.
        Nat. Commun. 2016; 7https://doi.org/10.1038/ncomms12504
        • Darmellah A.
        • Rayah A.
        • Auger R.
        • Cuif M.H.
        • Prigent M.
        • Arpin M.
        • Alcover A.
        • Delarasse C.
        • Kanellopoulos J.M.
        Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein.
        J. Biol. Chem. 2012; 287: 34583-34595https://doi.org/10.1074/jbc.M112.400010
        • De Marchi E.
        • Orioli E.
        • Dal Ben D.
        • Adinolfi E.
        P2X7 receptor as a therapeutic target.
        in: Advances in Protein Chemistry and Structural Biology. 1st ed. Elsevier Inc, 2016https://doi.org/10.1016/bs.apcsb.2015.11.004
        • Delpech J.-C.
        • Madore C.
        • Nadjar A.
        • Joffre C.
        • Wohleb E.S.
        • Layé S.
        Microglia in neuronal plasticity: influence of stress.
        Neuropharmacology. 2015; 96: 19-28https://doi.org/10.1016/j.neuropharm.2014.12.034
        • Dempsey C.
        • Rubio Araiz A.
        • Bryson K.J.
        • Finucane O.
        • Larkin C.
        • Mills E.L.
        • Robertson A.A.B.
        • Cooper M.A.
        • O’Neill L.A.J.
        • Lynch M.A.
        Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice.
        Brain Behav. Immun. 2017; 61: 306-316https://doi.org/10.1016/j.bbi.2016.12.014
        • van der Putten C.
        • Zuiderwijk-Sick E.A.
        • van Straalen L.
        • de Geus E.D.
        • Boven L.A.
        • Kondova I.
        • IJzerman A.P.
        • Bajramovic J.J.
        Differential expression of adenosine A3 receptors controls adenosine A2A receptor-mediated inhibition of TLR responses in microglia.
        J. Immunol. 2009; 182: 7603-7612https://doi.org/10.4049/jimmunol.0803383
        • Di Virgilio F.
        Liaisons dangereuses: P2X7and the inflammasome.
        Trends Pharmacol. Sci. 2007; https://doi.org/10.1016/j.tips.2007.07.002
        • Dickson D.W.
        Microglia in Alzheimer’s disease and transgenic models. How close the fit?.
        Am. J. Pathol. 1999; 154: 1627-1631https://doi.org/10.1016/S0002-9440(10)65416-8
        • Donnelly-Roberts D.L.
        • Namovic M.T.
        • Surber B.
        • Vaidyanathan S.X.
        • Perez-Medrano A.
        • Wang Y.
        • Carroll W.A.
        • Jarvis M.F.
        [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors.
        Neuropharmacology. 2009; 56: 223-229https://doi.org/10.1016/J.NEUROPHARM.2008.06.012
        • Doody R.S.
        • Raman R.
        • Farlow M.
        • Iwatsubo T.
        • Vellas B.
        • Joffe S.
        • Kieburtz K.
        • He F.
        • Sun X.
        • Thomas R.G.
        • Aisen P.S.
        • Siemers E.
        • Sethuraman G.
        • Mohs R.
        A phase 3 trial of semagacestat for treatment of Alzheimer’s disease.
        N. Engl. J. Med. 2013; 369: 341-350https://doi.org/10.1056/NEJMoa1210951
        • Doody R.S.
        • Thomas R.G.
        • Farlow M.
        • Iwatsubo T.
        • Vellas B.
        • Joffe S.
        • Kieburtz K.
        • Raman R.
        • Sun X.
        • Aisen P.S.
        • Siemers E.
        • Liu-Seifert H.
        • Mohs R.
        Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease.
        N. Engl. J. Med. 2014; 370: 311-321https://doi.org/10.1056/NEJMoa1312889
        • Doyle S.
        • Ozaki E.
        • Campbell M.
        Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives.
        J. Inflamm. Res. 2015; 8: 15https://doi.org/10.2147/JIR.S51250
        • Duplantier A.J.
        • Dombroski M.A.
        • Subramanyam C.
        • Beaulieu A.M.
        • Chang S.-P.
        • Gabel C.A.
        • Jordan C.
        • Kalgutkar A.S.
        • Kraus K.G.
        • Labasi J.M.
        • Mussari C.
        • Perregaux D.G.
        • Shepard R.
        • Taylor T.J.
        • Trevena K.A.
        • Whitney-Pickett C.
        • Yoon K.
        Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535.
        Bioorg. Med. Chem. Lett. 2011; 21: 3708-3711https://doi.org/10.1016/j.bmcl.2011.04.077
        • Egan M.F.
        • Kost J.
        • Tariot P.N.
        • Aisen P.S.
        • Cummings J.L.
        • Vellas B.
        • Sur C.
        • Mukai Y.
        • Voss T.
        • Furtek C.
        • Mahoney E.
        • Harper Mozley L.
        • Vandenberghe R.
        • Mo Y.
        • Michelson D.
        Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease.
        N. Engl. J. Med. 2018; 378: 1691-1703https://doi.org/10.1056/NEJMoa1706441
        • Fang L.
        • Gou S.
        • Fang X.
        • Cheng L.
        • Fleck C.
        Current progresses of novel natural products and their derivatives/analogs as anti-Alzheimer candidates: an update.
        Mini-Reviews Med. Chem. 2013; 13: 870-887https://doi.org/10.2174/1389557511313060009
        • Fantoni E.R.
        • Dal Ben D.
        • Falzoni S.
        • Di Virgilio F.
        • Lovestone S.
        • Gee A.
        Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7.
        EJNMMI Res. 2017; 7https://doi.org/10.1186/s13550-017-0275-2
        • Feng J.
        • Wang J.
        • Du Y.
        • Liu Y.
        • Zhang W.
        • Chen J.
        • Liu Y.
        • Zheng M.
        • Wang K.
        • He G.
        Dihydromyricetin inhibits microglial activation and neuroinflammation by suppressing NLRP3 inflammasome activation in APP/PS1 transgenic mice.
        CNS Neurosci. Ther. 2018; : 1-12https://doi.org/10.1111/cns.12983
        • Flores J.
        • Noël A.
        • Foveau B.
        • Lynham J.
        • Lecrux C.
        • LeBlanc A.C.
        Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model.
        Nat. Commun. 2018; 9https://doi.org/10.1038/s41467-018-06449-x
        • Franco R.
        • Fernández-Suárez D.
        Alternatively activated microglia and macrophages in the central nervous system.
        Prog. Neurobiol. 2015; 131: 65-86https://doi.org/10.1016/j.pneurobio.2015.05.003
        • Fredholm B.B.
        • IJzerman A.P.
        • Jacobson K.A.
        • Klotz K.N.
        • Linden J.
        International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors.
        Pharmacol. Rev. 2001; 53: 527-552
        • Freilich R.W.
        • Woodbury M.E.
        • Ikezu T.
        Integrated expression profiles of mRNA and miRNA in polarized primary murine microglia.
        PLoS One. 2013; 8e79416https://doi.org/10.1371/journal.pone.0079416
        • Freire D.
        • Reyes R.E.
        • Baghram A.
        • Davies D.L.
        • Asatryan L.
        P2X7 receptor antagonist A804598 inhibits inflammation in brain and liver in C57BL/6J mice exposed to chronic ethanol and high fat diet.
        J. NeuroImmune Pharmacol. 2018; : 1-15https://doi.org/10.1007/s11481-018-9816-3
        • Fu Y.
        • Yang J.
        • Wang X.
        • Yang P.
        • Zhao Y.
        • Li K.
        • Chen Y.
        • Xu Y.
        Herbal compounds play a role in neuroprotection through the inhibition of microglial activation.
        J Immunol Res. 2018; 2018https://doi.org/10.1155/2018/9348046
        • Ganguli M.
        The unbearable lightness of MCI.
        Int. Psychogeriatr. 2014; 26: 353-359https://doi.org/10.1017/S1041610213002275
        • Gao M.
        • Wang M.
        • Green M.A.
        • Hutchins G.D.
        • Zheng Q.-H.
        Synthesis of [11 C]GSK1482160 as a new PET agent for targeting P2X 7 receptor.
        Bioorg. Med. Chem. Lett. 2015; 25: 1965-1970https://doi.org/10.1016/j.bmcl.2015.03.021
        • Gao M.
        • Wang M.
        • Glick-Wilson B.E.
        • Meyer J.A.
        • Peters J.S.
        • Territo P.R.
        • Green M.A.
        • Hutchins G.D.
        • Zarrinmayeh H.
        • Zheng Q.H.
        Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [18F]IUR-1601.
        Bioorg. Med. Chem. Lett. 2018; 28: 1603-1609https://doi.org/10.1016/j.bmcl.2018.03.044
        • Gauthier S.
        • Reisberg B.
        • Zaudig M.
        • Petersen R.C.
        • Ritchie K.
        • Broich K.
        • Belleville S.
        • Brodaty H.
        • Bennett D.
        • Chertkow H.
        • Cummings J.L.
        • de Leon M.
        • Feldman H.
        • Ganguli M.
        • Hampel H.
        • Scheltens P.
        • Tierney M.C.
        • Whitehouse P.
        • Winblad B.
        International psychogeriatric association expert conference on mild cognitive impairment.
        Lancet. 2006; 367 (Mild cognitive impairment): 1262-1270https://doi.org/10.1016/S0140-6736(06)68542-5
        • Gebicke-Haerter P.J.
        • Christoffel F.
        • Timmer J.
        • Northoff H.
        • Berger M.
        • Van Calker D.
        Both adenosine A1- and A2-receptors are required to stimulate microglial proliferation.
        Neurochem. Int. 1996; 29: 37-42https://doi.org/10.1016/0197-0186(95)00137-9
        • Graeber M.B.
        • Streit W.J.
        Microglia: biology and pathology.
        Acta Neuropathol. 2010; 119: 89-105https://doi.org/10.1007/s00401-009-0622-0
        • Hammarberg C.
        • Schulte G.
        • Fredholm B.B.
        Evidence for functional adenosine A3 receptors in microglia cells.
        J. Neurochem. 2003; 86: 1051-1054https://doi.org/10.1046/j.1471-4159.2003.01919.x
        • Han J.
        • Liu H.
        • Liu C.
        • Jin H.
        • Perlmutter J.S.
        • Egan T.M.
        • Tu Z.
        Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11 C]GSK1482160 for neuroinflammatory response.
        Nucl. Med. Commun. 2017; 38: 372-382https://doi.org/10.1097/MNM.0000000000000660
        • Hanisch U.-K.
        • Kettenmann H.
        Microglia: active sensor and versatile effector cells in the normal and pathologic brain.
        Nat. Neurosci. 2007; 10: 1387-1394https://doi.org/10.1038/nn1997
        • Hardy J.
        • Selkoe D.J.
        The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics.
        Science. 2002; 297: 353-356https://doi.org/10.1126/science.1072994
        • Haynes S.E.
        • Hollopeter G.
        • Yang G.
        • Kurpius D.
        • Dailey M.E.
        • Gan W.-B.
        • Julius D.
        The P2Y12 receptor regulates microglial activation by extracellular nucleotides.
        Nat. Neurosci. 2006; 9: 1512-1519https://doi.org/10.1038/nn1805
        • Headley A.
        • De Leon-Benedetti A.
        • Dong C.
        • Levin B.
        • Loewenstein D.
        • Camargo C.
        • Rundek T.
        • Zetterberg H.
        • Blennow K.
        • Wright C.B.
        • Sun X.
        • Initiative Alzheimer’s Disease Neuroimaging
        Neurogranin as a predictor of memory and executive function decline in MCI patients.
        Neurology. 2018; 90: e887-e895https://doi.org/10.1212/WNL.0000000000005057
        • Heese K.
        • Fiebich B.L.
        • Bauer J.
        • Otten U.
        Nerve growth factor (NGF) expression in rat microglia is induced by adenosine A2a-receptors.
        Neurosci. Lett. 1997; 231: 83-86https://doi.org/10.1016/S0304-3940(97)00545-4
        • Heppner F.L.
        • Ransohoff R.M.
        • Becher B.
        Immune attack: the role of inflammation in Alzheimer disease.
        Nat. Rev. Neurosci. 2015; 16: 358-372https://doi.org/10.1038/nrn3880
        • Honig L.S.
        • Vellas B.
        • Woodward M.
        • Boada M.
        • Bullock R.
        • Borrie M.
        • Hager K.
        • Andreasen N.
        • Scarpini E.
        • Liu-Seifert H.
        • Case M.
        • Dean R.A.
        • Hake A.
        • Sundell K.
        • Poole Hoffmann V.
        • Carlson C.
        • Khanna R.
        • Mintun M.
        • DeMattos R.
        • Selzler K.J.
        • Siemers E.
        Trial of solanezumab for mild dementia due to Alzheimer’s disease.
        N. Engl. J. Med. 2018; 378: 321-330https://doi.org/10.1056/NEJMoa1705971
        • Hopkins C.R.
        ACS chemical neuroscience molecule spotlight on ELND006: another γ-secretase inhibitor fails in the clinic.
        ACS Chem. Neurosci. 2011; https://doi.org/10.1021/cn2000469
        • Hopper A.T.
        • Campbell B.M.
        • Kao H.
        • Pintchovski S.A.
        • Staal R.G.W.
        Recent developments in targeting neuroinflammation in disease.
        Annu. Rep. Med. Chem. 2012; 47: 37-53https://doi.org/10.1016/B978-0-12-396492-2.00004-7
        • Hu X.
        • Ivashkiv L.B.
        Cross-regulation of signaling pathways by interferon-γ: implications for immune responses and autoimmune diseases.
        Immunity. 2009; 31: 539-550https://doi.org/10.1016/J.IMMUNI.2009.09.002
        • Jacobson K.A.
        • Müller C.E.
        Medicinal chemistry of adenosine, P2Y and P2X receptors.
        Neuropharmacology. 2016; https://doi.org/10.1016/j.neuropharm.2015.12.001
        • Jama F.
        Mechanisms and Myths.
        67. 2011: 2010-2012
        • Janssen B.
        • Vugts D.J.
        • Funke U.
        • Spaans A.
        • Schuit R.C.
        • Kooijman E.
        • Rongen M.
        • Perk L.R.
        • Lammertsma A.A.
        • Windhorst A.D.
        Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A-740003 as a novel tracer of neuroinflammation.
        J. Label. Compd. Radiopharm. 2014; 57: 509-516https://doi.org/10.1002/jlcr.3206
        • Janssen B.
        • Vugts D.J.
        • Wilkinson S.M.
        • Ory D.
        • Chalon S.
        • Hoozemans J.J.M.
        • Schuit R.C.
        • Beaino W.
        • Kooijman E.J.M.
        • Van Den Hoek J.
        • Chishty M.
        • Doméné A.
        • Van Der Perren A.
        • Villa A.
        • Maggi A.
        • Molenaar G.T.
        • Funke U.
        • Shevchenko R.V.
        • Baekelandt V.
        • Bormans G.
        • Lammertsma A.A.
        • Kassiou M.
        • Windhorst A.D.
        Identification of the allosteric P2X7receptor antagonist [11C]SMW139 as a PET tracer of microglial activation.
        Sci. Rep. 2018; 8: 1-10https://doi.org/10.1038/s41598-018-24814-0
        • Jiang T.
        • Yu J.T.
        Novel disease-modifying therapies for Alzheimer’s disease.
        J. Alzheimers Dis. 2012; https://doi.org/10.3233/JAD-2012-120640
        • Jin H.
        • Han J.
        • Resing D.
        • Liu H.
        • Yue X.
        • Miller R.L.
        • Schoch K.M.
        • Miller T.M.
        • Perlmutter J.S.
        • Egan T.M.
        • Tu Z.
        Synthesis and in vitro characterization of a P2X7 radioligand [123 I]TZ6019 and its response to neuroinflammation in a mouse model of Alzheimer disease.
        Eur. J. Pharmacol. 2018; 820: 8-17https://doi.org/10.1016/j.ejphar.2017.12.006
        • Kettenmann H.
        • Hanisch U.-K.
        • Noda M.
        • Verkhratsky A.
        Physiology of microglia.
        Physiol. Rev. 2011; 91: 461-553https://doi.org/10.1152/physrev.00011.2010
        • Kim H.J.
        • Ajit D.
        • Peterson T.S.
        • Wang Y.
        • Camden J.M.
        • Gibson Wood W.
        • Sun G.Y.
        • Erb L.
        • Petris M.
        • Weisman G.A.
        Nucleotides released from Aβ1-42-treated microglial cells increase cell migration and Aβ1-42 uptake through P2Y2 receptor activation.
        J. Neurochem. 2012; 121: 228-238https://doi.org/10.1111/j.1471-4159.2012.07700.x
        • Kitazawa M.
        • Yamasaki T.R.
        • Laferla F.M.
        Microglia as a potential bridge between the amyloid -peptide and tau.
        Ann. N. Y. Acad. Sci. 2004; 1035: 85-103https://doi.org/10.1196/annals.1332.006
        • Krstic D.
        • Knuesel I.
        Deciphering the mechanism underlying late-onset Alzheimer disease.
        Nat. Rev. Neurol. 2013; 9: 25-34https://doi.org/10.1038/nrneurol.2012.236
      1. La Rosa, F., Saresella, M., Marventano, I., Piancone, F., Ripamonti, E., Paola Zoia, C., Conti, E., Ferrarese, C., Clerici, M., 2018. Stavudine Reduces NLRP3 Inflammasome Activation and Upregulates A-Autophagy D4T Reduces NLRP3 Activation. bioRxiv. https://doi.org/10.1101/377945

        • Lacey D.C.
        • Achuthan A.
        • Fleetwood A.J.
        • Dinh H.
        • Roiniotis J.
        • Scholz G.M.
        • Chang M.W.
        • Beckman S.K.
        • Cook A.D.
        • Hamilton J.A.
        Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models.
        J. Immunol. 2012; 188: 5752-5765https://doi.org/10.4049/jimmunol.1103426
        • Lai A.Y.
        • Dhami K.S.
        • Dibal C.D.
        • Todd K.G.
        Neonatal rat microglia derived from different brain regions have distinct activation responses.
        Neuron Glia Biol. 2011; 7: 5-16https://doi.org/10.1017/S1740925X12000154
        • Lamkanfi M.
        Emerging inflammasome effector mechanisms.
        Nat. Rev. Immunol. 2011; 11: 213-220https://doi.org/10.1038/nri2936
        • Latz E.
        • Xiao T.S.
        • Stutz A.
        Activation and regulation of the inflammasomes.
        Nat. Rev. Immunol. 2013; 13: 397-411https://doi.org/10.1038/nri3452
        • Lee J.Y.
        • Jhun B.S.
        • Oh Y.T.
        • Lee J.H.
        • Choe W.
        • Baik H.H.
        • Ha J.
        • Yoon K.-S.
        • Kim S.S.
        • Kang I.
        Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-α production through inhibition of PI 3-kinase/Akt and NF-κB activation in murine BV2 microglial cells.
        Neurosci. Lett. 2006; 396: 1-6https://doi.org/10.1016/j.neulet.2005.11.004
        • Lee C.M.
        • Lee D.S.
        • Jung W.K.
        • Yoo J.S.
        • Yim M.J.
        • Choi Y.H.
        • Park S.
        • Seo S.K.
        • Choi J.S.
        • Lee Y.M.
        • Park W.S.
        • Choi I.W.
        Benzyl isothiocyanate inhibits inflammasome activation in E. coli LPS-stimulated BV2 cells.
        Int. J. Mol. Med. 2016; 38: 912-918https://doi.org/10.3892/ijmm.2016.2667
        • Letavic M.A.
        • Lord B.
        • Bischoff F.
        • Hawryluk N.A.
        • Pieters S.
        • Rech J.C.
        • Sales Z.
        • Velter A.I.
        • Ao H.
        • Bonaventure P.
        • Contreras V.
        • Jiang X.
        • Morton K.L.
        • Scott B.
        • Wang Q.
        • Wickenden A.D.
        • Carruthers N.I.
        • Bhattacharya A.
        Synthesis and pharmacological characterization of two novel, brain penetrating P2X7antagonists.
        ACS Med. Chem. Lett. 2013; 4: 419-422https://doi.org/10.1021/ml400040v
        • Letavic M.A.
        • Savall B.M.
        • Allison B.D.
        • Aluisio L.
        • Andres J.I.
        • De Angelis M.
        • Ao H.
        • Beauchamp D.A.
        • Bonaventure P.
        • Bryant S.
        • Carruthers N.I.
        • Ceusters M.
        • Coe K.J.
        • Dvorak C.A.
        • Fraser I.C.
        • Gelin C.F.
        • Koudriakova T.
        • Liang J.
        • Lord B.
        • Lovenberg T.W.
        • Otieno M.A.
        • Schoetens F.
        • Swanson D.M.
        • Wang Q.
        • Wickenden A.D.
        • Bhattacharya A.
        4-Methyl-6,7-dihydro-4 H -triazolo[4,5- c ]pyridine-Based P2X7 receptor antagonists: optimization of pharmacokinetic properties leading to the identification of a clinical candidate.
        J. Med. Chem. 2017; 60: 4559-4572https://doi.org/10.1021/acs.jmedchem.7b00408
        • Letavic M.A.
        • Savall B.M.
        • Allison B.D.
        • Aluisio L.
        • Andres J.I.
        • De Angelis M.
        • Ao H.
        • Beauchamp D.A.
        • Bonaventure P.
        • Bryant S.
        • Carruthers N.I.
        • Ceusters M.
        • Coe K.J.
        • Dvorak C.A.
        • Fraser I.C.
        • Gelin C.F.
        • Koudriakova T.
        • Liang J.
        • Lord B.
        • Lovenberg T.W.
        • Otieno M.A.
        • Schoetens F.
        • Swanson D.M.
        • Wang Q.
        • Wickenden A.D.
        • Bhattacharya A.
        4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-based P2X7 receptor antagonists: optimization of pharmacokinetic properties leading to the identification of a clinical candidate.
        J. Med. Chem. 2017; 60: 4559-4572https://doi.org/10.1021/acs.jmedchem.7b00408
        • Levey A.
        • Lah J.
        • Goldstein F.
        • Steenland K.
        • Bliwise D.
        Mild cognitive impairment: an opportunity to identify patients at high risk for progression to Alzheimer’s disease.
        Clin. Ther. 2006; 28: 991-1001https://doi.org/10.1016/j.clinthera.2006.07.006
        • Li Y.
        • Liu L.
        • Barger S.W.
        • Griffin W.S.T.
        Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway.
        J. Neurosci. 2003; 23: 1605-1611
        • Li H.-q.
        • Chen C.
        • Dou Y.
        • Wu H.-j.
        • Liu Y.-j.
        • Lou H.-F.
        • Zhang J.-m.
        • Li X.-m.
        • Wang H.
        • Duan S.
        P2Y4 receptor-mediated pinocytosis contributes to amyloid beta-induced self-uptake by microglia.
        Mol. Cell. Biol. 2013; 33: 4282-4293https://doi.org/10.1128/MCB.00544-13
        • Li J.-J.
        • Liu S.-J.
        • Liu X.-Y.
        • Ling E.-A.
        Herbal compounds with special reference to gastrodin as potential therapeutic agents for microglia mediated neuroinflammation.
        Curr. Med. Chem. 2018; 25https://doi.org/10.2174/0929867325666180214123929
        • Li Q.
        • Chen L.
        • Liu X.
        • Li X.
        • Cao Y.
        • Bai Y.
        • Qi F.
        Pterostilbene inhibits amyloid-β-induced neuroinflammation in a microglia cell line by inactivating the NLRP3/caspase-1 inflammasome pathway.
        J. Cell. Biochem. 2018; 119: 7053-7062https://doi.org/10.1002/jcb.27023
        • Liang E.
        • Liu W.J.
        • Lohr L.
        • Nguyen V.
        • Lin H.
        • Munson M. Lou
        • Crans G.
        • Cedarbaum J.
        A Phase 1, dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral daily doses of ELND006 in healthy elderly subjects.
        Alzheimers Dement. 2011; 7: S465https://doi.org/10.1016/j.jalz.2011.05.1347
        • Liu B.
        • Wang K.
        • Gao H.M.
        • Mandavilli B.
        • Wang J.Y.
        • Hong J.S.
        Molecular consequences of activated microglia in the brain: overactivation induces apoptosis.
        J. Neurochem. 2001; 77: 182-189https://doi.org/10.1046/J.1471-4159.2001.T01-1-00216.X
        • Loane D.J.
        • Byrnes K.R.
        Role of microglia in neurotrauma.
        Neurotherapeutics. 2010; 7: 366-377https://doi.org/10.1016/j.nurt.2010.07.002
        • Lord B.
        • Ameriks M.K.
        • Wang Q.
        • Fourgeaud L.
        • Vliegen M.
        • Verluyten W.
        • Haspeslagh P.
        • Carruthers N.I.
        • Lovenberg T.W.
        • Bonaventure P.
        • Letavic M.A.
        • Bhattacharya A.
        A novel radioligand for the ATP-gated ion channel P2X7: [3H] JNJ-54232334.
        Eur. J. Pharmacol. 2015; 765: 551-559https://doi.org/10.1016/j.ejphar.2015.09.026
        • Lovell M.A.
        • Markesbery W.R.
        Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease.
        Nucleic Acids Res. 2007; 35: 7497-7504https://doi.org/10.1093/nar/gkm821
        • Mandrekar-Colucci S.
        • Karlo J.C.
        • Landreth G.E.
        Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease.
        J. Neurosci. 2012; 32: 10117-10128https://doi.org/10.1523/JNEUROSCI.5268-11.2012
        • Martin E.
        • Amar M.
        • Dalle C.
        • Youssef I.
        • Boucher C.
        • Le Duigou C.
        • Brückner M.
        • Prigent A.
        • Sazdovitch V.
        • Halle A.
        • Kanellopoulos J.M.
        • Fontaine B.
        • Delatour B.
        • Delarasse C.
        New role of P2X7 receptor in an Alzheimer’s disease mouse model.
        Mol. Psychiatry. 2018; 1https://doi.org/10.1038/s41380-018-0108-3
        • McGeer P.L.
        • McGeer E.G.
        Targeting microglia for the treatment of Alzheimer’s disease.
        Expert Opin. Ther. Targets. 2015; 19: 497-506https://doi.org/10.1517/14728222.2014.988707
        • McGeer P.L.
        • McGeer E.G.
        • Yasojima K.
        Alzheimer disease and neuroinflammation.
        J. Neural Transm. Suppl. 2000; 59: 53-57https://doi.org/10.1007/978-3-7091-6781-6_8
        • Mclarnon J.G.
        • Ryu J.K.
        • Walker D.G.
        • Choi H.B.
        Upregulated expression of purinergic P2X7 receptor in Alzheimer disease and amyloid-A peptide-treated microglia and in peptide-injected rat hippocampus.
        J. Neuropathol. Exp. Neurol. 2006; 65: 1090-1097
        • Michell-Robinson M.A.
        • Touil H.
        • Healy L.M.
        • Owen D.R.
        • Durafourt B.A.
        • Bar-Or A.
        • Antel J.P.
        • Moore C.S.
        Roles of microglia in brain development, tissue maintenance and repair.
        Brain. 2015; 138: 1138-1159https://doi.org/10.1093/brain/awv066
        • Modrego P.J.
        • Ferrández J.
        Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type.
        Arch. Neurol. 2004; 61: 1290-1293https://doi.org/10.1001/archneur.61.8.1290
        • Mu Y.
        • Gage F.H.
        Adult hippocampal neurogenesis and its role in Alzheimer’s disease.
        Mol. Neurodegener. 2011; 6: 85https://doi.org/10.1186/1750-1326-6-85
        • Münch G.
        • Schinzel R.
        • Loske C.
        • Wong A.
        • Durany N.
        • Li J.J.
        • Vlassara H.
        • Smith M.A.
        • Perry G.
        • Riederer P.
        Alzheimer’s disease – synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts.
        J. Neural Transm. 1998; 105: 439-461https://doi.org/10.1007/s007020050069
        • Munoz L.
        • Ammit A.J.
        Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease.
        Neuropharmacology. 2010; https://doi.org/10.1016/j.neuropharm.2009.11.010
        • Murphy N.
        • Cowley T.R.
        • Richardson J.C.
        • Virley D.
        • Upton N.
        • Walter D.
        • Lynch M.A.
        The neuroprotective effect of a specific P2X7 receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells.
        Brain Pathol. 2012; 22: 295-306https://doi.org/10.1111/j.1750-3639.2011.00531.x
        • Naert G.
        • Rivest S.
        The role of microglial cell subsets in Alzheimers disease.
        Curr. Alzheimer Res. 2011; 8: 151-155https://doi.org/10.2174/156720511795256035
        • Narayanaswami V.
        • Dahl K.
        • Bernard-Gauthier V.
        • Josephson L.
        • Cumming P.
        • Vasdev N.
        Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: outlook beyond TSPO.
        Mol. Imaging. 2018; 17153601211879231https://doi.org/10.1177/1536012118792317
        • Nemetchek M.D.
        • Stierle A.A.
        • Stierle D.B.
        • Lurie D.I.
        The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain.
        J. Ethnopharmacol. 2017; 197: 92-100https://doi.org/10.1016/j.jep.2016.07.073
        • Norden D.M.
        • Muccigrosso M.M.
        • Godbout J.P.
        Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease.
        Neuropharmacology. 2015; 96: 29-41https://doi.org/10.1016/j.neuropharm.2014.10.028
        • O’Brien R.J.
        • Wong P.C.
        Amyloid precursor protein processing and Alzheimer’s disease.
        Annu. Rev. Neurosci. 2011; 34: 185-204https://doi.org/10.1146/annurev-neuro-061010-113613
        • Ory D.
        • Celen S.
        • Gijsbers R.
        • Van Den Haute C.
        • Postnov A.
        • Koole M.
        • Vandeputte C.
        • Andres J.-I.
        • Alcazar J.
        • De Angelis M.
        • Langlois X.
        • Bhattacharya A.
        • Schmidt M.
        • Letavic M.A.
        • Vanduffel W.
        • Van Laere K.
        • Verbruggen A.
        • Debyser Z.
        • Bormans G.
        Preclinical evaluation of a P2X7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in nonhuman primates.
        J. Nucl. Med. 2016; 57: 1436-1441https://doi.org/10.2967/jnumed.115.169995
        • Ozaki E.
        • Campbell M.
        • Doyle S.L.
        Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives.
        J. Inflamm. Res. 2015; https://doi.org/10.2147/JIR.S51250
      2. Park, J., Kim, Y., 2017. P2X7 receptor antagonists: a patent review (2010–2015). Expert Opin. Ther. Pat. 27(3):257-267. https://doi.org/10.1080/13543776.2017.1246538

        • Petersen R.C.
        Mild cognitive impairment as a diagnostic entity.
        J. Intern. Med. 2004; 256: 183-194https://doi.org/10.1111/j.1365-2796.2004.01388.x
        • Peterson T.S.
        • Thebeau C.N.
        • Ajit D.
        • Camden J.M.
        • Woods L.T.
        • Wood W.G.
        • Petris M.J.
        • Sun G.Y.
        • Erb L.
        • Weisman G.A.
        Up-regulation and activation of the P2Y2 nucleotide receptor mediate neurite extension in IL-1β-treated mouse primary cortical neurons.
        J. Neurochem. 2013; 125: 885-896https://doi.org/10.1111/jnc.12252
        • Polazzi E.
        • Contestabile A.
        Overactivation of LPS-stimulated microglial cells by co-cultured neurons or neuron-conditioned medium.
        J. Neuroimmunol. 2006; 172: 104-111https://doi.org/10.1016/j.jneuroim.2005.11.005
        • van Praag H.
        • Schinder A.F.
        • Christie B.R.
        • Toni N.
        • Palmer T.D.
        • Gage F.H.
        Functional neurogenesis in the adult hippocampus.
        Nature. 2002; 415: 1030-1034https://doi.org/10.1038/4151030a
        • Prince M.
        • Comas-Herrera A.
        • Knapp M.
        • Guerchet M.
        • Karagiannidou M.
        World Alzheimer Report 2016: Improving Healthcare for People Living with Dementia: Coverage, Quality and Costs Now and in the Future.
        2016
        • Pul R.
        • Moharregh-Khiabani D.
        • Škuljec J.
        • Skripuletz T.
        • Garde N.
        • Voss E.V.
        • Stangel M.
        Glatiramer acetate modulates TNF-α and IL-10 secretion in microglia and promotes their phagocytic activity.
        J. NeuroImmune Pharmacol. 2011; 6: 381-388https://doi.org/10.1007/s11481-010-9248-1
        • Rech J.C.
        • Bhattacharya A.
        • Letavic M.A.
        • Savall B.M.
        The evolution of P2X7 antagonists with a focus on CNS indications.
        Bioorg. Med. Chem. Lett. 2016; https://doi.org/10.1016/j.bmcl.2016.06.048
        • Rodriguez-Alvarez N.
        • Jimenez-Mateos E.M.
        • Engel T.
        • Quinlan S.
        • Reschke C.R.
        • Conroy R.M.
        • Bhattacharya A.
        • Boylan G.B.
        • Henshall D.C.
        Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice.
        Neuropharmacology. 2017; 116: 351-363https://doi.org/10.1016/j.neuropharm.2017.01.005
        • Rosenblum W.I.
        Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult.
        Neurobiol. Aging. 2014; 35: 969-974https://doi.org/10.1016/j.neurobiolaging.2013.10.085
        • Ryu J.K.
        • McLarnon J.G.
        Block of purinergic P2X7 receptor is neuroprotective in an animal model of Alzheimer’s disease.
        Neuroreport. 2008; 19: 1715-1719https://doi.org/10.1097/WNR.0b013e3283179333
        • Sáez-Orellana F.
        • Godoy P.
        • Bastidas C.
        • Silva-Grecchi T.
        • Guzmán L.
        • et al.
        ATP leakage induces P2XR activation and contributes to acute synaptic excitotoxicity induced by soluble oligomers of b-amyloid peptide in hippocampal neurons.
        Neuropharmacology. 2016; 100: 116-123https://doi.org/10.1016/j.neuropharm.2015.04.005
        • Sáez-Orellana F.
        • Fuentes-Fuentes M.C.
        • Godoy P.A.
        • Silva-Grecchi T.
        • Panes J.D.
        • Guzmán L.
        • Yévenes G.E.
        • Gavilán J.
        • Egan T.M.
        • Aguayo L.G.
        • Fuentealba J.
        P2X receptor overexpression induced by soluble oligomers of amyloid beta peptide potentiates synaptic failure and neuronal dyshomeostasis in cellular models of Alzheimer’s disease.
        Neuropharmacology. 2018; 128: 366-378https://doi.org/10.1016/j.neuropharm.2017.10.027
        • Sanz J.M.
        • Chiozzi P.
        • Ferrari D.
        • Colaianna M.
        • Idzko M.
        • Falzoni S.
        • Fellin R.
        • Trabace L.
        • Di Virgilio F.
        Activation of microglia by amyloid {beta} requires P2X7 receptor expression.
        J. Immunol. 2009; 182: 4378-4385https://doi.org/10.4049/jimmunol.0803612
        • Sarlus H.
        • Heneka M.T.
        Microglia in Alzheimer’s disease.
        J. Clin. Invest. 2017; 127: 33-35https://doi.org/10.1172/JCI90606
        • Sastre M.
        • Klockgether T.
        • Heneka M.T.
        Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms.
        Int. J. Dev. Neurosci. 2006; 24: 167-176https://doi.org/10.1016/j.ijdevneu.2005.11.014
        • Saura J.
        • Angulo E.
        • Ejarque A.
        • Casado V.
        • Tusell J.M.
        • Moratalla R.
        • Chen J.-F.
        • Schwarzschild M.A.
        • Lluis C.
        • Franco R.
        • Serratosa J.
        Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia.
        J. Neurochem. 2005; 95: 919-929https://doi.org/10.1111/j.1471-4159.2005.03395.x
        • Savall B.M.
        • Wu D.
        • De Angelis M.
        • Carruthers N.I.
        • Ao H.
        • Wang Q.
        • Lord B.
        • Bhattacharya A.
        • Letavic M.A.
        Synthesis, SAR, and pharmacological characterization of brain penetrant P2X7 receptor antagonists.
        ACS Med. Chem. Lett. 2015; 6: 671-676https://doi.org/10.1021/acsmedchemlett.5b00089
        • Selkoe D.J.
        Alzheimer’s disease is a synaptic failure.
        Science. 2002; 298: 789-791https://doi.org/10.1126/science.1074069
        • Shao B.Z.
        • Xu Z.Q.
        • Han B.Z.
        • Su D.F.
        • Liu C.
        NLRP3 inflammasome and its inhibitors: a review.
        Front. Pharmacol. 2015; https://doi.org/10.3389/fphar.2015.00262
        • Shi J.Q.
        • Zhang C.C.
        • Sun X.L.
        • Cheng X.X.
        • Wang J.B.
        • Zhang Y.D.
        • Xu J.
        • Zou H.Q.
        Antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation in APPswe/PS1dE9 transgenic mice via inhibition of nuclear factor-κB and NLRP3 inflammasome activation.
        CNS Neurosci. Ther. 2013; 19: 262-268https://doi.org/10.1111/cns.12066
        • Shieh C.-H.
        • Heinrich A.
        • Serchov T.
        • van Calker D.
        • Biber K.
        P2X7-dependent, but differentially regulated release of IL-6, CCL2, and TNF-α in cultured mouse microglia.
        Glia. 2014; 62: 592-607https://doi.org/10.1002/glia.22628
        • Simon E.
        • Obst J.
        • Gomez-Nicola D.
        The evolving dialogue of microglia and neurons in Alzheimer’s disease: microglia as necessary transducers of pathology.
        Neuroscience. 2018; https://doi.org/10.1016/j.neuroscience.2018.01.059
        • Smith T.D.
        • Tse M.J.
        • Read E.L.
        • Liu W.F.
        Regulation of macrophage polarization and plasticity by complex activation signals.
        HHS Public Access Graphical abstract. Integr Biol. 2016; 8: 946-955https://doi.org/10.1039/c6ib00105j
        • Soulet D.
        • Rivest S.
        Bone-marrow-derived microglia: myth or reality?.
        Curr. Opin. Pharmacol. 2008; 8: 508-518https://doi.org/10.1016/j.coph.2008.04.002
        • Sperlágh B.
        • Illes P.
        P2X7 receptor: an emerging target in central nervous system diseases.
        Trends Pharmacol. Sci. 2014; https://doi.org/10.1016/j.tips.2014.08.002
        • Subramaniam S.R.
        • Federoff H.J.
        Targeting microglial activation states as a therapeutic avenue in Parkinson’s disease.
        Front. Aging Neurosci. 2017; 9https://doi.org/10.3389/fnagi.2017.00176
        • Takeda K.
        • Akira S.
        TLR signaling pathways.
        Semin. Immunol. 2004; 16: 3-9https://doi.org/10.1016/j.smim.2003.10.003
        • Takenouchi T.
        • Sekiyama K.
        • Sekigawa A.
        • Fujita M.
        • Waragai M.
        • Sugama S.
        • Iwamaru Y.
        • Kitani H.
        • Hashimoto M.
        P2X7 receptor signaling pathway as a therapeutic target for neurodegenerative diseases.
        Arch. Immunol. Ther. Exp. 2010; 58: 91-96https://doi.org/10.1007/s00005-010-0069-y
        • Teich A.F.
        • Arancio O.
        Is the amyloid hypothesis of Alzheimer’s disease therapeutically relevant?.
        Biochem. J. 2012; 446: 165-177https://doi.org/10.1042/BJ20120653
        • Territo P.R.
        • Meyer J.A.
        • Peters J.S.
        • Riley A.A.
        • McCarthy B.P.
        • Gao M.
        • Wang M.
        • Green M.A.
        • Zheng Q.-H.
        • Hutchins G.D.
        Characterization of 11C-GSK1482160 for targeting the P2X7 receptor as a biomarker for neuroinflammation.
        J. Nucl. Med. 2017; 58: 458-465https://doi.org/10.2967/jnumed.116.181354
        • Thompson K.
        • Tsirka S.
        The diverse roles of microglia in the neurodegenerative aspects of central nervous system (CNS) autoimmunity.
        Int. J. Mol. Sci. 2017; 18: 504https://doi.org/10.3390/ijms18030504
        • Varma R.
        • Chai Y.
        • Troncoso J.
        • Gu J.
        • Xing H.
        • Stojilkovic S.S.
        • Mattson M.P.
        • Haughey N.J.
        Amyloid-β induces a caspase-mediated cleavage of P2X4 to promote purinotoxicity.
        NeuroMolecular Med. 2009; 11: 63-75https://doi.org/10.1007/s12017-009-8073-2
        • Venigalla M.
        • Sonego S.
        • Gyengesi E.
        • Sharman M.J.
        • Münch G.
        Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer’s disease.
        Neurochem. Int. 2016; 95: 63-74https://doi.org/10.1016/j.neuint.2015.10.011
        • Walker D.G.
        • Lue L.-F.
        Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains.
        Alzheimers Res. Ther. 2015; 7https://doi.org/10.1186/s13195-015-0139-9
        • Walsh D.M.
        • Selkoe D.J.
        Deciphering the molecular basis of memory failure in Alzheimer’s disease.
        Neuron. 2004; 44: 181-193https://doi.org/10.1016/J.NEURON.2004.09.010
        • Wang S.
        • Jing H.
        • Yang H.
        • Liu Z.
        • Guo H.
        • Chai L.
        • Hu L.
        Tanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson's disease.
        J. Ethnopharmacol. 2015; 164: 247-255https://doi.org/10.1016/j.jep.2015.01.042
        • Wang W.-Y.
        • Tan M.-S.
        • Yu J.-T.
        • Tan L.
        Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease.
        Ann. Transl. Med. 2015; 3: 136https://doi.org/10.3978/j.issn.2305-5839.2015.03.49
        • Wang H.M.
        • Zhang T.
        • Huang J.K.
        • Xiang J.Y.
        • Chen J.J.
        • Fu J.L.
        • Zhao Y.W.
        Edaravone attenuates the proinflammatory response in amyloid-β-treated microglia by inhibiting NLRP3 inflammasome-mediated IL-1β secretion.
        Cell. Physiol. Biochem. 2017; 43: 1113-1125https://doi.org/10.1159/000481753
        • Weisman G.A.
        • Camden J.M.
        • Peterson T.S.
        • Ajit D.
        • Woods L.T.
        • Erb L.
        P2 receptors for extracellular nucleotides in the central nervous system: role of P2X7 and P2Y2 receptor interactions in neuroinflammation.
        Mol. Neurobiol. 2012; 46: 96-113https://doi.org/10.1007/s12035-012-8263-z
        • Wiley J.S.
        • Sluyter R.
        • Gu B.J.
        • Stokes L.
        • Fuller S.J.
        The human P2X7 receptor and its role in innate immunity.
        Tissue Antigens. 2011; 78: 321-332https://doi.org/10.1111/j.1399-0039.2011.01780.x
        • Wilkinson S.M.
        • Gunosewoyo H.
        • Barron M.L.
        • Boucher A.
        • McDonnell M.
        • Turner P.
        • Morrison D.E.
        • Bennett M.R.
        • McGregor I.S.
        • Rendina L.M.
        • Kassiou M.
        The first cns-active carborane: a novel p2x7 receptor antagonist with antidepressant activity.
        ACS Chem. Neurosci. 2014; 5: 335-339https://doi.org/10.1021/cn500054n
        • Woods L.T.
        • Ajit D.
        • Camden J.M.
        • Erb L.
        • Weisman G.A.
        Purinergic receptors as potential therapeutic targets in Alzheimer’s disease.
        Neuropharmacology. 2016; 104: 169-179https://doi.org/10.1016/j.neuropharm.2015.10.031
      3. World Alzheimer Report 2015: The Global Impact of Dementia | Alzheimer’s Disease International [WWW Document], n.d. URL https://www.alz.co.uk/research/world-report-2015 (accessed 7.30.18).

        • Wu Z.
        • Yu J.
        • Zhu A.
        • Nakanishi H.
        Nutrients, microglia aging, and brain aging.
        Oxidative Med. Cell. Longev. 2016; 2016: 1-9https://doi.org/10.1155/2016/7498528
        • Xu J.
        • Barger S.W.
        • Drew P.D.
        The PPAR-gamma agonist 15-deoxy-delta-prostaglandin J(2) attenuates microglial production of IL-12 family cytokines: potential relevance to Alzheimer’s disease.
        PPAR Res. 2008; 2008https://doi.org/10.1155/2008/349185
        • Yin J.
        • Zhao F.
        • Chojnacki J.E.
        • Fulp J.
        • Klein W.L.
        • Zhang S.
        • Zhu X.
        NLRP3 inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer’s disease.
        Mol. Neurobiol. 2018; 55: 1977-1987https://doi.org/10.1007/s12035-017-0467-9
        • Young C.N.J.
        • Górecki D.C.
        P2RX7 purinoceptor as a therapeutic target – the second coming?.
        Front. Chem. 2018; 6: 1-14https://doi.org/10.3389/fchem.2018.00248
        • Zhang L.
        • Zhang Z.
        • Fu Y.
        • Yang P.
        • Qin Z.
        • Chen Y.
        • Xu Y.
        Trans -cinnamaldehyde improves memory impairment by blocking microglial activation through the destabilization of iNOS mRNA in mice challenged with lipopolysaccharide.
        Neuropharmacology. 2016; 110: 503-518https://doi.org/10.1016/j.neuropharm.2016.08.013
        • Zhang S.
        • Gao L.
        • Liu X.
        • Lu T.
        • Xie C.
        • Jia J.
        Resveratrol attenuates microglial activation via SIRT1-SOCS1 pathway.
        Evid. Based Complement. Alternat. Med. 2017; 20178791832https://doi.org/10.1155/2017/8791832
        • Zhong L.-M.
        • Zong Y.
        • Sun L.
        • Guo J.-Z.
        • Zhang W.
        • He Y.
        • Song R.
        • Wang W.-M.
        • Xiao C.-J.
        • Lu D.
        Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells.
        PLoS One. 2012; 7e32195https://doi.org/10.1371/journal.pone.0032195
        • Ziff J.
        • Rudolph D.A.
        • Stenne B.
        • Koudriakova T.
        • Lord B.
        • Bonaventure P.
        • Lovenberg T.W.
        • Carruthers N.I.
        • Bhattacharya A.
        • Letavic M.A.
        • Shireman B.T.
        Substituted 5,6-(Dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-methanones as P2X7 antagonists.
        ACS Chem. Neurosci. 2016; 7: 498-504https://doi.org/10.1021/acschemneuro.5b00304