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Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease

Inflammopharmacology volume 28, pages 95–110 (2020)Cite this article

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease that results in progressive dementia, and exhibits high disability and fatality rates. Recent evidence has demonstrated that neuroinflammation is critical in the pathophysiological processes of AD, which is characterized by the activation of microglia and astrocytes. Under different stimuli, microglia are usually activated into two polarized states, termed the classical ‘M1’ phenotype and the alternative ‘M2’ phenotype. M1 microglia are considered to promote inflammatory injury in AD; in contrast, M2 microglia exert neuroprotective effects. Imbalanced microglial polarization, in the form of excessive activation of M1 microglia and dysfunction of M2 microglia, markedly promotes the development of AD. Furthermore, an increasing number of studies have shown that the transition of microglia from the M1 to M2 phenotype could potently alleviate pathological damage in AD. Hence, this article reviews the current knowledge regarding the role of microglial M1/M2 polarization in the pathophysiology of AD. In addition, we summarize several approaches that protect against AD by altering the polarization states of microglia. This review aims to contribute to a better understanding of the pathogenesis of AD and, moreover, to explore the potential of novel drugs for the treatment of AD in the future.

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References

  • Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    CAS  PubMed  PubMed Central  Google Scholar 

  • Artavanistsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776

    CAS  Google Scholar 

  • Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593

    CAS  PubMed  PubMed Central  Google Scholar 

  • Balce DR, Li B, Allan ER, Rybicka JM, Krohn RM, Yates RM (2011) Alternative activation of macrophages by IL-4 enhances the proteolytic capacity of their phagosomes through synergistic mechanisms. Blood 118:4199–4208. https://doi.org/10.1182/blood-2011-01-328906

    CAS  Article  PubMed  Google Scholar 

  • Bhaskar K, Konerth M, Kokikocochran ON, Cardona A, Ransohoff RM, Lamb BT (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boche D, Cunningham C, Docagne F, Scott H, Perry VH (2006) TGFbeta1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol Dis 22:638–650. https://doi.org/10.1016/j.nbd.2006.01.004

    CAS  Article  PubMed  Google Scholar 

  • Bolós V, Grego-Bessa J, Pompa JLDL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363

    PubMed  Google Scholar 

  • Brifault C, Gras M, Liot D, May V, Vaudry D, Wurtz O (2015) Delayed pituitary adenylate cyclase-activating polypeptide delivery after brain stroke improves functional recovery by inducing m2 microglia/macrophage polarization. Stroke J Cereb Circ 46:520–528

    CAS  Google Scholar 

  • Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, Schwartz M (2006) Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci USA 103:11784–11789

    CAS  PubMed  PubMed Central  Google Scholar 

  • Butovsky O, Bukshpan S, Kunis G, Jung S, Schwartz M (2007) Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers. Mol Cell Neurosci 35:490–500. https://doi.org/10.1016/j.mcn.2007.04.009

    CAS  Article  PubMed  Google Scholar 

  • Chen C, Li YH, Zhang Q, Yu JZ, Zhao YF, Ma CG, Xiao BG (2014) Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis. Acta Pharmacol Sin 35:1428–1438

    CAS  PubMed  PubMed Central  Google Scholar 

  • Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418

    PubMed  PubMed Central  Google Scholar 

  • D’Andrea MR, Cole GM, Ard MD (2004) The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging 25:675–683

    PubMed  Google Scholar 

  • Dimitris S, Nussenzweig MC (2007) CD8–DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. J Exp Med 204:1525–1531

    Google Scholar 

  • Dyck S, Kataria H, Alizadeh A, Santhosh KT, Lang B, Silver J, Karimiabdolrezaee S (2018) Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPσ receptors promotes a beneficial inflammatory response following spinal cord injury. J. Neuroinflamm 15:90

    Google Scholar 

  • Edwards JP, Zhang X, Frauwirth KA, Mosser DM (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80:1298–1307

    CAS  PubMed  Google Scholar 

  • Escribano L, Simón AM, Gimeno E, Cuadradotejedor M, Maturana RLD, Garcíaosta A, Ricobaraza A, Pérezmediavilla A, Río JD, Frechilla D (2010) Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 35:1593

    CAS  Google Scholar 

  • Fillit H, Ding W, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G (1991) Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci Lett 129:318–320

    CAS  PubMed  Google Scholar 

  • Gandy S, Heppner FL (2013) Microglia as dynamic and essential components of the amyloid hypothesis. Neuron 78:575–577

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20:269–287

    CAS  PubMed  Google Scholar 

  • Giri S, Nath N, Smith B, Viollet B, Singh AK, Singh I (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci Off J Soc Neurosci 24:479–487

    CAS  Google Scholar 

  • Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D, Li X, Kirkpatrick JB (1995) Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem Int 27:119–137

    CAS  PubMed  Google Scholar 

  • Guo H, Cheng Y, Wang C, Wu J, Zou Z, Niu B, Yu H, Wang H, Xu J (2017a) FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. Neuropharmacology 116:260–269

    CAS  PubMed  Google Scholar 

  • Guo M, Li C, Lei Y, Xu S, Zhao D, Lu XY (2017b) Role of the adipose PPARγ-adiponectin axis in susceptibility to stress and depression/anxiety-related behaviors. Mol Psychiatr 22:1056

    CAS  Google Scholar 

  • Han X, Lan X, Li Q, Gao Y, Zhu W, Cheng T, Maruyama T, Wang J (2015) Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 36:1059

    Google Scholar 

  • Huang S, Ge X, Yu J, Han Z, Yin Z, Li Y, Chen F, Wang H, Zhang J, Lei P (2017) Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. Faseb J Off Publ Fed Am Soc Exp Biol 32:512–528

    Google Scholar 

  • Huang Y, He J, Liang H, Hu K, Jiang S, Yang L, Mei S, Zhu X, Yu J, Kijlstra A, Yang P, Hou S (2018) Aryl hydrocarbon receptor regulates apoptosis and inflammation in a murine model of experimental autoimmune uveitis. Front Immunol 9:1713. https://doi.org/10.3389/fimmu.2018.01713

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, Ravasi T (2002) The mononuclear phagocyte system revisited. J Leukoc Biol 72:621–627

    CAS  PubMed  Google Scholar 

  • In TVB, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345:1515–1521. https://doi.org/10.1056/NEJMoa010178

    Article  Google Scholar 

  • Ji J, Xue TF, Guo XD, Yang J, Guo RB, Wang J, Huang JY, Zhao XJ, Sun XL (2018) Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway. Aging Cell 17:e12774

    PubMed  PubMed Central  Google Scholar 

  • Jiang T, Zhang YD, Chen Q, Gao Q, Zhu XC, Zhou JS, Shi JQ, Lu H, Tan L, Yu JT (2016) TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105:196–206

    CAS  PubMed  Google Scholar 

  • Jiang T, Zhang L, Pan X, Zheng H, Chen X, Li L, Luo J, Hu X (2017) Physical exercise improves cognitive function together with microglia phenotype modulation and remyelination in chronic cerebral hypoperfusion. Front Cell Neurosci 11:404

    PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Li Z, Ma H, Cao X, Liu F, Tian A, Sun X, Li X, Wang J (2018) Upregulation of TREM2 ameliorates neuroinflammatory responses and improves cognitive deficits triggered by surgical trauma in appswe/PS1dE9 mice. Cell Physiol Biochem 46:1398–1411

    CAS  PubMed  Google Scholar 

  • Kawahara K, Suenobu M, Yoshida A, Koga K, Hyodo A, Ohtsuka H, Kuniyasu A, Tamamaki N, Sugimoto Y, Nakayama H (2012) Intracerebral microinjection of interleukin-4/interleukin-13 reduces β-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice. Neuroscience 207:243–260

    CAS  PubMed  Google Scholar 

  • Ke X, Xue-Ling D, Han-Chang H, Zhao-Feng J (2011) Targeting HDACs: a promising therapy for Alzheimer’s disease. Oxid Med Cell Longev 2011:143269

    Google Scholar 

  • Kim YE, Hwang CJ, Lee HP, Kim CS, Son DJ, Ham YW, Hellström M, Han SB, Kim HS, Park EK (2017) Inhibitory effect of punicalagin on lipopolysaccharide-induced neuroinflammation, oxidative stress and memory impairment via inhibition of nuclear factor-kappaB. Neuropharmacology 117:21–32

    CAS  PubMed  Google Scholar 

  • Kiyota T, Okuyama S, Swan RJ, Jacobsen MT, Gendelman HE, Ikezu T (2010) CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP + PS1 bigenic mice. Faseb J Off Publ Fed Am Soc Exp Biol 24:3093

    CAS  Google Scholar 

  • Knaus UG (2000) Rho GTPase signaling in inflammation and transformation. Immunol Res 21:103–109

    CAS  PubMed  Google Scholar 

  • Koenigsknechttalboo J, Landreth GE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 25:8240–8249

    CAS  Google Scholar 

  • Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL (2013) Functional impairment of microglia coincides with beta-amyloid deposition in mice with alzheimer-like pathology. PLoS One 8:e60921

    CAS  PubMed  PubMed Central  Google Scholar 

  • Labandeiragarcia JL, Rodríguezperez AI, Garridogil P, Rodriguezpallares J, Lanciego JL, Guerra MJ (2017) Brain renin-angiotensin system and microglial polarization: implications for aging and neurodegeneration. Front Aging Neurosci 9:129

    Google Scholar 

  • Laibaik P, Ping Z, Rose P, Carmen C, Josef A, Norris EH, Linda Y, Steven Y, George C, Mcewen BS (2008) Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc Natl Acad Sci USA 105:1347–1352

    Google Scholar 

  • Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189

    CAS  PubMed  Google Scholar 

  • Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405

    CAS  PubMed  Google Scholar 

  • Leipnitz G, Schumacher C, Dalcin KB, Scussiato K, Solano A, Funchal C, Dutrafilho CS, Wyse AT, Wannmacher CM, Latini A (2007) In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain. Neurochem Int 50:83–94

    CAS  PubMed  Google Scholar 

  • Li YH, Yu JZ, Xin YL, Feng L, Chai Z, Liu JC, Zhang HZ, Zhang GX, Xiao BG, Ma CG (2015) Protective effect of a novel Rho kinase inhibitor WAR–5 in experimental autoimmune encephalomyelitis by modulating inflammatory response and neurotrophic factors. Exp Mol Pathol 99:220–228

    CAS  PubMed  Google Scholar 

  • Li D, Wang C, Yao Y, Chen L, Liu G, Zhang R, Liu Q, Shi FD, Hao J (2016) mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. Faseb J Off Publ Fed Am Soc Exp Biol 30:3388

    CAS  Google Scholar 

  • Li C, Zhang C, Zhou H, Feng Y, Tang F, Hoi MPM, He C, Ma D, Zhao C, Lee SMY (2018) Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation. Front Mol Neurosci 11:98

    PubMed  PubMed Central  Google Scholar 

  • Licht-Murava A, Paz R, Vaks L, Avrahami L, Plotkin B, Eisenstein M, Eldar-Finkelman H (2016) A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci Signal 9:ra110

    PubMed  Google Scholar 

  • Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, Fairman RM, Velazquez OC, Herlyn M (2003) Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23:14–25

    PubMed  PubMed Central  Google Scholar 

  • Liu HC, Zheng MH, Du YL, Wang L, Kuang F, Qin HY, Zhang BF, Han H (2012a) N9 microglial cells polarized by LPS and IL4 show differential responses to secondary environmental stimuli. Cell Immunol 278:84–90

    CAS  PubMed  Google Scholar 

  • Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rube CE, Walter J, Heneka MT, Hartmann T, Menger MD, Fassbender K (2012b) TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 188:1098–1107. https://doi.org/10.4049/jimmunol.1101121

    CAS  Article  PubMed  Google Scholar 

  • Liu M, Jevtic S, Markham-Coultes K, Ellens N, O’Reilly MA, Hynynen K, Aubert I, McLaurin J (2018) Investigating the efficacy of a combination Abeta-targeted treatment in a mouse model of Alzheimer’s disease. Brain Res 1678:138–145. https://doi.org/10.1016/j.brainres.2017.10.015

    CAS  Article  PubMed  Google Scholar 

  • Lue LF, Kuo YM, Beach T, Walker DG (2010) Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol Neurobiol 41:115–128. https://doi.org/10.1007/s12035-010-8106-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Luo XQ, Li A, Yang X, Xiao X, Hu R, Wang TW, Dou XY, Yang DJ, Dong Z (2018) Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2. Chin Med 13:14

    PubMed  PubMed Central  Google Scholar 

  • Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR (2007) Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell 18:1490

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mandrekarcolucci S, Karlo JC, Landreth GE (2012) 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 Off J Soc Neurosci 32:10117–10128

    CAS  Google Scholar 

  • Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    CAS  PubMed  Google Scholar 

  • Maqbool M, Hoda N (2017) GSK3 inhibitors in the therapeutic development of diabetes, cancer and neurodegeneration: past, present and future. Curr Pharm Des 23:4332–4350. https://doi.org/10.2174/1381612823666170714141450

    CAS  Article  PubMed  Google Scholar 

  • Mcdonald DR, Brunden KR, Landreth GE (1997) Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci Off J Soc Neurosci 17:2284

    CAS  Google Scholar 

  • Mecha M, Feliú A, Carrillosalinas FJ, Ruedazubiaurre A, Ortegagutiérrez S, de Sola RG, Guaza C (2015) Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav Immun 49:233–245

    CAS  PubMed  Google Scholar 

  • Michaud JP, Hallé M, Lampron A, Thériault P, Préfontaine P, Filali M, Triboutjover P, Lanteigne AM, Jodoin R, Cluff C (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci USA 110:1941–1946

    CAS  PubMed  PubMed Central  Google Scholar 

  • Michelucci A (2009) Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol 210:3–12

    CAS  PubMed  Google Scholar 

  • Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212

    CAS  PubMed  Google Scholar 

  • Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura Y, Si QS, Kataoka K (1999) Lipopolysaccharide-induced microglial activation in culture: temporal profiles of morphological change and release of cytokines and nitric oxide. Neurosci Res 35:95–100

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Oh S, Son M, Choi J, Lee S, Byun K (2017) sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer’s disease model. Biochem Biophys Res Commun 495:807–813

    PubMed  Google Scholar 

  • Orihuela R, Mcpherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665

    CAS  PubMed  Google Scholar 

  • Pasinetti GM (2002) From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer’s disease: the role of NSAIDs and cyclooxygenase in β-amyloidosis and clinical dementia. J Alzheimers Dis 4:435–445

    CAS  PubMed  Google Scholar 

  • Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27:10714–10721. https://doi.org/10.1523/JNEUROSCI.1922-07.2007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Popiolekbarczyk K, Kolosowska N, Piotrowska A, Makuch W, Rojewska E, Jurga AM, Pilat D, Mika J (2015) Parthenolide relieves pain and promotes M2 microglia/macrophage polarization in rat model of neuropathy. Neural Plast 2015:1–15

    Google Scholar 

  • Raleigh DJ (2006) Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat Rev Neurol 2:679–689

    Google Scholar 

  • Roser AE, Tönges L, Lingor P (2017) Modulation of microglial activity by rho-kinase (ROCK) inhibition as therapeutic strategy in Parkinson’s disease and amyotrophic lateral sclerosis. Fronti Aging Neurosci. 9:94

    Google Scholar 

  • Sackmann V, Ansell A, Sackmann C, Lund H, Harris RA, Hallbeck M, Nilsberth C (2017) Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells. Neurobiol Aging 60:173

    CAS  PubMed  Google Scholar 

  • Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sheffield LG, Marquis JG, Berman NE (2000) Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimer’s disease. Neurosci Lett 285:165–168

    CAS  PubMed  Google Scholar 

  • Sheng JG, Mrak RE, Griffin WST (1997) Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1α + microglia and S100β + astrocytes with neurofibrillary tangle stages. J Neuropath Exp Neur 56:285–290

    CAS  PubMed  Google Scholar 

  • Ślusarczyk J, Trojan E, Głombik K, Piotrowska A, Budziszewska B, Kubera M, Popiołekbarczyk K, Lasoń W, Mika J, Bastakaim A (2018) Targeting the NLRP3 inflammasome-related pathways via tianeptine treatment-suppressed microglia polarization to the M1 phenotype in lipopolysaccharide-stimulated cultures. Int J Mol, Sci, p 19

    Google Scholar 

  • Smith EM, Gregg M, Hashemi F, Schott L, Hughes TK (2006) Corticotropin releasing factor (CRF) activation of NF-kappaB-directed transcription in leukocytes. Cell Mol Neurobiol 26:1019–1034

    Google Scholar 

  • Solito E, Sastre M (2012) Microglia function in Alzheimer’s disease. Front Pharmacol 3:14. https://doi.org/10.3389/fphar.2012.00014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Sollvander S, Nikitidou E, Brolin R, Soderberg L, Sehlin D, Lannfelt L, Erlandsson A (2016) Accumulation of amyloid-beta by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener 11:38. https://doi.org/10.1186/s13024-016-0098-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Spagnuolo C, Moccia S, Russo GL (2018) Anti-inflammatory effects of flavonoids in neurodegenerative disorders. Eur J Med Chem 153:105

    CAS  PubMed  Google Scholar 

  • Stewart CR, Stuart LM, Wilkinson K, Gils JMV, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155–161

    CAS  PubMed  Google Scholar 

  • Suh HS, Zhao ML, Derico L, Choi N, Lee SC (2013) Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflamm 10:37. https://doi.org/10.1186/1742-2094-10-37

    CAS  Article  Google Scholar 

  • Tang Y, Le W (2016) Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol 53:1181–1194

    CAS  PubMed  Google Scholar 

  • Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, Lin AH, Crews L, Tremblay P, Mathews P (2006) Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology. J. Clin. Invest. 116:3060–3069

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tichauer JE, von Bernhardi R (2012) Transforming growth factor-beta stimulates beta amyloid uptake by microglia through Smad3-dependent mechanisms. J Neurosci Res 90:1970–1980. https://doi.org/10.1002/jnr.23082

    CAS  Article  PubMed  Google Scholar 

  • Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, VieiraSaecker A, Schwartz S, Santarelli F, Kummer MP (2017) Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552:355

    CAS  PubMed  Google Scholar 

  • Waetzig V, Czeloth K, Hidding U, Mielke K, Kanzow M, Brecht S, Goetz M, Lucius R, Herdegen T, Hanisch UK (2005) c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. Glia 50:235–246. https://doi.org/10.1002/glia.20173

    Article  PubMed  Google Scholar 

  • Wang G, Shi Y, Jiang X, Leak RK, Hu X, Wu Y, Pu H, Li WW, Tang B, Wang Y, Gao Y (2015a) HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. Proc Natl Acad Sci USA 112:2853–2858

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Jing H, Yang H, Liu Z, Guo H, Chai L, Hu L (2015b) 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 164:247–255

    CAS  PubMed  Google Scholar 

  • Wang H, Liu C, Han M, Cheng C, Zhang D (2016) TRAM1 promotes microglia M1 polarization. J Mol Neurosci 58:287–296

    CAS  PubMed  Google Scholar 

  • Wang C, Wang Q, Lou Y, Xu J, Feng Z, Chen Y, Tang Q, Zheng G, Zhang Z, Wu Y (2017) Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation. J Cell Mol Med 22:1148–1166

    PubMed  PubMed Central  Google Scholar 

  • Wei Z, Jun-Qi Y (2017) Role of Rho GTPases in the immune regulation of infection and inflammation. Zhongguo xue xi chong bing fang zhi za zhi = Chinese journal of schistosomiasis control 29:807

    PubMed  Google Scholar 

  • Wilkinson K, El JK (2012) Microglial scavenger receptors and their roles in the pathogenesis of alzheimer’s disease. Int J Alzheimers Dis 2012:489456

    PubMed  PubMed Central  Google Scholar 

  • Wirz KT (2013) Cortical beta amyloid protein triggers an immune response, but no synaptic changes in the APPswe/PS1dE9 Alzheimer’s disease mouse model. Neurobiol Aging 34:1328–1342

    CAS  PubMed  Google Scholar 

  • Wu F, Luo T, Mei Y, Liu H, Dong J, Fang Y, Peng J, Guo Y (2017) Simvastatin alters M1/M2 polarization of murine BV2 microglia via Notch signaling. J Neuroimmunol 316:56–64

    PubMed  Google Scholar 

  • Wu HY, Tang XQ, Liu H, Mao XF, Wang YX (2018) Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers. J Neuroimmunol 316:17–22

    CAS  PubMed  Google Scholar 

  • Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015

    CAS  PubMed  Google Scholar 

  • Wyss-Coray T, Lin CF, Yu G, Rohde M, Mcconlogue L, Masliah E, Mucke L (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7:612–618

    CAS  PubMed  Google Scholar 

  • Xu Y, Xu Y, Wang Y, Wang Y, He L, Jiang Z, Huang Z, Liao H, Li J, Saavedra JM (2015) Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation. Brain Behav Immun 50:298–313

    CAS  PubMed  Google Scholar 

  • Yamamoto M, Kiyota T, Walsh SM, Liu J, Kipnis J, Ikezu T (2008) Cytokine-mediated inhibition of fibrillar amyloid-β peptide degradation by human mononuclear phagocytes. J Immunol 181:3877–3886

    CAS  PubMed  Google Scholar 

  • Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT (2012) PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32:17321–17331

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yao K, Zhao YF (2018) Aging modulates microglia phenotypes in neuroinflammation of MPTP-PD mice. Exp Gerontol 111:86–93. https://doi.org/10.1016/j.exger.2018.07.010

    CAS  Article  PubMed  Google Scholar 

  • Yu J, Gu Q, Yan Y, Yu H, Guo M, Liu C, Song G, Chai Z, Wang Q, Xiao B (2017) Fasudil improves cognition of APP/PS1 transgenic mice via inhibiting the activation of microglia and shifting microglia phenotypes from M1 to M2. XI Bao Yu Fen Zi Mian Yi Xue Za Zhi 33:1585–1593

    PubMed  Google Scholar 

  • Zare-Shahabadi A, Masliah E, Johnson GV, Rezaei N (2015) Autophagy in Alzheimer’s disease. Rev Neurosci 26:385–395. https://doi.org/10.1515/revneuro-2014-0076

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, He ML (2017) Deferoxamine enhances alternative activation of microglia and inhibits amyloid beta deposits in APP/PS1 mice. Brain Res 1677:86–92

    CAS  PubMed  Google Scholar 

  • Zhang J, Guo J, Zhao X, Chen Z, Wang G, Liu A, Wang Q, Zhou W, Xu Y, Wang C (2013) Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. Behav Brain Res 250:230–237

    CAS  PubMed  Google Scholar 

  • Zhang F, Zhong R, Li S, Fu Z, Cheng C, Cai H, Le W (2017) Acute hypoxia induced an imbalanced M1/M2 activation of microglia through NF-κB signaling in Alzheimer’s disease mice and wild-type littermates. Front Aging Neurosci 9:282

    PubMed  PubMed Central  Google Scholar 

  • Zhao YF, Zhang Q, Xi JY, Li YH, Ma CG, Xiao BG (2015) Multitarget intervention of Fasudil in the neuroprotection of dopaminergic neurons in MPTP-mouse model of Parkinson’s disease. J Neurol Sci 353:28–37

    CAS  PubMed  Google Scholar 

  • Zhao Q, Wu X, Yan S, Xie X, Fan Y, Zhang J, Peng C, You Z (2016) The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes. J Neuroinflamm 13:259

    Google Scholar 

  • Zhao H, Wang Q, Cheng X, Li X, Li N, Liu T, Li J, Yang Q, Dong R, Zhang Y (2018) Inhibitive effect of resveratrol on the inflammation in cultured astrocytes and microglia induced by Aβ1–42. Neuroscience 379:390–404

    CAS  PubMed  Google Scholar 

  • Zhou Q, Wang M, Du Y, Zhang W, Bai M, Zhang Z, Li Z, Miao J (2015) Inhibition of JNK activation reverses AD-phenotypes in APPswe/PS1dE9 mice. Ann Neurol 77:637–654

    CAS  PubMed  Google Scholar 

  • Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, Zhu WY, Liao MF, Wu LR, Yang YR (2016) Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 37:967

    Google Scholar 

  • Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X, Zhang L, Tian H, Zhao Q, Peng J (2014) TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun 5:4696

    CAS  PubMed  Google Scholar 

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Acknowledgements

The study was supported by research grants from Research Project of Jinshan District Health and Family Planning Commission (No. JSKJ-KTMS-2018-19), Qi Hang project of Jinshan Hospital (No. 2018-JSYYQH-06). We thank LetPub (https://www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Neurology, Jinshan Hospital Affiliated to Fudan University, No. 1508 Longhang Road, Jinshan District, Shanghai, 201508, China

    Kai Yao & Heng-bing Zu

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  1. Kai Yao
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  2. Heng-bing Zu
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KY was responsible for the design and manuscript drafting. HZ contributed to figure generation and manuscript writing. All authors read and approved the final manuscript.

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Correspondence to Heng-bing Zu.

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Yao, K., Zu, Hb. Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease. Inflammopharmacol 28, 95–110 (2020). https://doi.org/10.1007/s10787-019-00613-5

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Keywords

  • Alzheimer’s disease
  • Microglia
  • Inflammation
  • Inflammatory signalling pathway
  • NF-κB