Neuroinflammation and Alzheimer’s disease: Implications for microglial activation

Current Alzheimer Research

Volumn 14, Issue 11, 2017, Pages 1140-1148

  Regen, Francesca ^a   Hellmann Regen, Julian ^a   Costantini, Erica ^b   Reale, Marcella ^b  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b UNIVERSITY OF CHIETI   (Italy)

Author keywords

Alzheimer s Disease; Amyloid beta; Microglia; Microglial activation; Neuro inflammation; Retinoic acid; Retinoid signaling; Tau; Vitamin A

Indexed keywords

CYTOKINE;

ALZHEIMER DISEASE; ASTROCYTE; CELL ACTIVATION; HUMAN; LYMPHOCYTE; MICROGLIA; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; ANIMAL; BRAIN; IMMUNOLOGY; IMMUNOMODULATION; INFLAMMATION; PATHOPHYSIOLOGY; PHYSIOLOGY;

ALZHEIMER DISEASE; ANIMALS; BRAIN; HUMANS; INFLAMMATION; MICROGLIA; NEUROIMMUNOMODULATION;

EID: 85016416498     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205014666170203141717     Document Type: Review

References (133)

1. Jack CR, Jr., Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12(2): 207-16 (2013).
2. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330(6012): 1774 (2010).
3. Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci 15(3): 349-57 (2012).
4. Ke YD, Dramiga J, Schutz U, Kril JJ, Ittner LM, Schroder H, et al. Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease. PLoS One 7(4): e35678 (2012).
5. Koechling T, Lim F, Hernandez F, Avila J. Neuronal models for studying tau pathology. Intern J Alzheimer Dis 2010: pii: 528474 (2010).
6. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71(5): 362-81 (2012).
7. Liu K, Solano I, Mann D, Lemere C, Mercken M, Trojanowski JQ, et al. Characterization of Abeta11-40/42 peptide deposition in Alzheimer's disease and young Down's syndrome brains: implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer's disease. Acta Neuropathol 112(2): 163-74(2006).
8. Canevelli M, Piscopo P, Talarico G, Vanacore N, Blasimme A, Crestini A, et al. Familial Alzheimer's disease sustained by presenilin 2 mutations: systematic review of literature and genotypephenotype correlation. Neurosci Biobehavioral Rev 42: 170-9 (2014).
9. Lippa CF. Familial Alzheimer's disease: genetic influences on the disease process (Review). Intern J Mol Med 4(5): 529-36 (1999).
10. Wang ZX, Tan L, Liu J, Yu JT. The essential role of soluble abeta oligomers in Alzheimer's disease. Mol Neurobiol 53(3): 1905-24 (2016).
11. Roeder AM, Roettger Y, Stundel A, Dodel R, Geyer A. Synthetic dimeric Abeta(28-40) mimics the complex epitope of human anti-Abeta autoantibodies against toxic Abeta oligomers. J Biol Chem 288(38): 27638-45 (2013).
12. Varvel NH, Bhaskar K, Patil AR, Pimplikar SW, Herrup K, Lamb BT. Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease. J Neurosci 28(43): 10786-93 (2008).
13. Kuo YM, Emmerling MR, Vigo-Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, et al. Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem 271(8): 4077-81 (1996).
14. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer's disease. N Engl J Med 368(2): 117-27 (2013).
15. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368(2): 107-16 (2013).
16. Besedovsky H, del Rey A, Sorkin E, Da Prada M, Burri R, Honegger C. The immune response evokes changes in brain noradrenergic neurons. Science 221(4610): 564-6 (1983).
17. Buttini M, Limonta S, Boddeke HW. Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain. Neurochem Intern 29(1): 25-35 (1996).
18. Fakhoury M. Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases. Neuro-degen Dis 15(2): 63-9 (2015).
19. Cappellano G, Carecchio M, Fleetwood T, Magistrelli L, Cantello R, Dianzani U, et al. Immunity and inflammation in neurodegenerative diseases. Am J Neurodegen Dis 2(2): 89-107 (2013).
20. Schwab C, McGeer PL. Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis 13(4): 359-69 (2008).
21. Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation 12: 114 (2015).
22. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 70(3): 374-83 (2011).
23. Emmrich JV, Ejaz S, Neher JJ, Williamson DJ, Baron JC. Regional distribution of selective neuronal loss and microglial activation across the MCA territory after transient focal ischemia: quantitative versus semiquantitative systematic immunohistochemical assessment. J Cerebral Blood Flow Metabol 35(1): 20-7 (2015).
24. del Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Berg GI, et al. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 38(2): 646-51 (2007).
25. Schlachetzki JC, Hull M. Microglial activation in Alzheimer's disease. Curr Alzheimer Res 6(6): 554-63 (2009).
26. Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease. Eur J Nuc Med Mol Imag 38(2): 343-51 (2011).
27. Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, et al. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp Neurol 171(1): 29-45 (2001).
28. Vilcek J, Feldmann M. Historical review: cytokines as therapeutics and targets of therapeutics. Trends Pharmacol Sci 25(4): 201-9 (2004).
29. Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58(3): 253-63 (2010).
30. Ponomarev ED, Maresz K, Tan Y, Dittel BN. 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(40): 10714-21 (2007).
31. Zarruk JG, Fernandez-Lopez D, Garcia-Yebenes I, Garcia-Gutierrez MS, Vivancos J, Nombela F, et al. Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 43(1): 211-9 (2012).
32. Thomson CA, McColl A, Cavanagh J, Graham GJ. Peripheral inflammation is associated with remote global gene expression changes in the brain. J Neuroinflam 11: 73 (2014).
33. Parakalan R, Jiang B, Nimmi B, Janani M, Jayapal M, Lu J, et al. Transcriptome analysis of amoeboid and ramified microglia isolated from the corpus callosum of rat brain. BMC Neurosci 13: 64 (2012).
34. Cardona AE, Li M, Liu L, Savarin C, Ransohoff RM. Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation. J Leukocyte Biol 84(3): 587-94 (2008).
35. Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 500(1-3): 399-411 (2004).
36. Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann New York Acad Sci 933: 222-34 (2001).
37. Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15(1): 7-24 (2001).
38. Lanzrein AS, Johnston CM, Perry VH, Jobst KA, King EM, Smith AD. Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. Alzheimer Dis Assoc Disord 12(3): 215-27 (1998).
39. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, et al. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain? J Neuroimmunol 103(1): 97-102 (2000).
40. Reale M, Iarlori C, Gambi F, Feliciani C, Isabella L, Gambi D. The acetylcholinesterase inhibitor, donepezil, regulates a Th2 bias in Alzheimer's disease patients. Neuropharmacology 50(5): 606-13 (2006).
41. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiat 68(10): 930-41 (2010).
42. Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, et al. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J Cin Investig 116(11): 3060-9 (2006).
43. Caraci F, Bosco P, Signorelli M, Spada RS, Cosentino FI, Toscano G, et al. The CC genotype of transforming growth factor-beta1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression. Eur Neuropsychopharmacol 22(4): 281-9 (2012).
44. Reale M, Kamal MA, Velluto L, Gambi D, Di Nicola M, Greig NH. Relationship between inflammatory mediators, Abeta levels and ApoE genotype in Alzheimer disease. Curr Alzheimer Res 9(4): 447-57 (2012).
45. Reale M, Greig NH, Kamal MA. Peripheral chemo-cytokine profiles in Alzheimer's and Parkinson's diseases. Mini Rev Med Chem 9(10): 1229-41 (2009).
46. Salani F, Ciaramella A, Bizzoni F, Assogna F, Caltagirone C, Spalletta G, et al. Increased expression of interleukin-18 receptor in blood cells of subjects with mild cognitive impairment and Alzheimer's disease. Cytokine 61(2): 360-3 (2013).
47. Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, Di Iulio F, et al. Interleukin-18 produced by peripheral blood cells is increased in Alzheimer's disease and correlates with cognitive impairment. Brain Behav Immun 22(4): 487-92 (2008).
48. Altstiel LD, Sperber K. Cytokines in Alzheimer's disease. Prog Neuro-psychopharmacol Biol Psychiat 15(4): 481-95 (1991).
49. Ho GJ, Drego R, Hakimian E, Masliah E. Mechanisms of cell signaling and inflammation in Alzheimer's disease. Curr Drug Targets Inflamm Allergy 4(2): 247-56 (2005).
50. Szczepanik AM, Funes S, Petko W, Ringheim GE. IL-4, IL-10 and IL-13 modulate A beta(1--42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 113(1): 49-62 (2001).
51. Li BH, Zhang LL, Yin YW, Pi Y, Guo L, Yang QW, et al. Association between interleukin-1alpha C(-889)T polymorphism and Alzheimer's disease: a meta-analysis including 12,817 subjects. J Neural Transm 120(3): 497-506 (2013).
52. Weinstein G, Wolf PA, Beiser AS, Au R, Seshadri S. Risk estimations, risk factors, and genetic variants associated with Alzheimer's disease in selected publications from the Framingham Heart Study. J Alzheimers Dis 33(1): S439-45 (2013).
53. Hua Y, Zhao H, Kong Y, Lu X. Meta-analysis of the association between the interleukin-1A-889C/T polymorphism and Alzheimer's disease. J Neurosci Res 90(9): 1681-92 (2012).
54. Di Bona D, Rizzo C, Bonaventura G, Candore G, Caruso C. Association between interleukin-10 polymorphisms and Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis 29(4): 751-9 (2012).
55. Dai L, Liu D, Guo H, Wang Y, Bai Y. Association between polymorphism in the promoter region of Interleukin 6 (-174 G/C) and risk of Alzheimer's disease: a meta-analysis. J Neurol 259(3): 414-9 (2012).
56. Di Bona D, Candore G, Franceschi C, Licastro F, Colonna-Romano G, Camma C, et al. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease. Brain Res Rev 61(2): 60-8 (2009).
57. Baruch K, Schwartz M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav Immun 34: 11-6 (2013).
58. Radjavi A, Smirnov I, Kipnis J. Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav Immun 35: 58-63 (2014).
59. Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Investig 112(3): 415-22 (2003).
60. Schenk D, Hagen M, Seubert P. Current progress in beta-amyloid immunotherapy. Curr Opin Immunol 16(5): 599-606 (2004).
61. Dorostkar MM, Burgold S, Filser S, Barghorn S, Schmidt B, Anumala UR, et al. Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model. Brain 137(Pt 12): 3319-26 (2014).
62. Karran E. Current status of vaccination therapies in Alzheimer's disease. J Neurochem 123(5): 647-51 (2012).
63. McGeer PL. Amyloid-beta vaccination for Alzheimer's dementia. Lancet 372(9647): 81-2 (2008).
64. Dong Y, Benveniste EN. Immune function of astrocytes. Glia 36(2): 180-90 (2001).
65. Montgomery DL. Astrocytes: form, functions, and roles in disease. Veterin Pathol 31(2): 145-67 (1994).
66. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25(7): 1481-8 (1994).
67. Sallmann S, Juttler E, Prinz S, Petersen N, Knopf U, Weiser T, et al. Induction of interleukin-6 by depolarization of neurons. J Neurosci 20(23): 8637-42 (2000).
68. Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565: 30-8 (2014).
69. Tremblay ME, Lecours C, Samson L, Sanchez-Zafra V, Sierra A. From the Cajal alumni Achucarro and Rio-Hortega to the rediscovery of never-resting microglia. Front Neuroanatom 9: 45 (2015).
70. Antel J. Multiple sclerosis--emerging concepts of disease pathogenesis. J Neuroimmunol 98(1): 45-8 (1999).
71. Hohlfeld R, Meinl E, Weber F, Zipp F, Schmidt S, Sotgiu S, et al. The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis. Neurology 45(6 Suppl 6): S33-8 (1995).
72. Streit WJ, Braak H, Xue QS, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathologica 118(4): 475-85 (2009).
73. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron 77(1): 10-8 (2013).
74. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11): 1387-94 (2007).
75. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 91(2): 461-553 (2011).
76. Town T, Nikolic V, Tan J. The microglial “activation” continuum: from innate to adaptive responses. J Neuroinflamm 2: 24 (2005).
77. Eikelenboom P, van Gool WA. Neuroinflammatory perspectives on the two faces of Alzheimer's disease. J Neural Transm 111(3): 281-94 (2004).
78. Paresce DM, Ghosh RN, Maxfield FR. Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 17(3): 553-65 (1996).
79. Yu Y, Ye RD. Microglial Abeta receptors in Alzheimer's disease. CellMol Neurobiol 35(1): 71-83 (2015).
80. Wilkinson K, El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Intern J Azheimer Dis 2012: 489456 (2012).
81. Hellmann-Regen J, Kronenberg G, Uhlemann R, Freyer D, Endres M, Gertz K. Accelerated degradation of retinoic acid by activated microglia. J Neuroimmunol 256(1-2): 1-6 (2013).
82. Herber DL, Mercer M, Roth LM, Symmonds K, Maloney J, Wilson N, et al. Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol 2(2): 222-31 (2007).
83. Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D. Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15(1): 11-20 (2004).
84. Shigematsu K, McGeer PL, Walker DG, Ishii T, McGeer EG. Reactive microglia/macrophages phagocytose amyloid precursor protein produced by neurons following neural damage. J Neurosci Res 31(3): 443-53 (1992).
85. Sondag CM, Dhawan G, Combs CK. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflammation 6: 1 (2009).
86. Kingham PJ, Pocock JM. Microglial secreted cathepsin B induces neuronal apoptosis. J Neurochem 76(5): 1475-84 (2001).
87. Kaindl AM, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, et al. Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann Neurol 72(4): 536-49 (2012).
88. Taylor DL, Jones F, Kubota ES, Pocock JM. Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglialderived Fas ligand. J Neurosci 25(11): 2952-64 (2005).
89. Barger SW, Basile AS. Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J Neurochem 76(3): 846-54 (2001).
90. Giulian D, Corpuz M, Chapman S, Mansouri M, Robertson C. Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system. J Neurosci Res 36(6): 681-93 (1993).
91. Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, et al. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol Aging 35(10): 2249-62 (2014).
92. Leoutsakos JM, Muthen BO, Breitner JC, Lyketsos CG, Team AR. Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Antiinflammatory Prevention Trial. Intern J Geriatric Psychiat 27(4): 364-74 (2012).
93. Breitner JC, Gau BA, Welsh KA, Plassman BL, McDonald WM, Helms MJ, et al. Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. Neurology 44(2): 227-32 (1994).
94. Czeh M, Gressens P, Kaindl AM. The yin and yang of microglia. Devel Neurosci 33(3-4): 199-209 (2011).
95. Sun Y, Fan J, Zhu Z, Guo X, Zhou T, Duan W, et al. Small molecule TBTC as a new selective retinoid X receptor alpha agonist improves behavioral deficit in Alzheimer's disease model mice. Eur J Pharmacol 762: 202-13 (2015).
96. Chen KC, Liu YC, Lee CC, Chen CY. Potential retinoid x receptor agonists for treating Alzheimer's disease from traditional chinese medicine. Evid Based Complement Alternat Med: eCAM 2014: 278493 (2014).
97. Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. Proc Natl Acad Sci U S A 100(5): 2901-5 (2003).
98. Xu J, Storer PD, Chavis JA, Racke MK, Drew PD. Agonists for the peroxisome proliferator-activated receptor-alpha and the retinoid X receptor inhibit inflammatory responses of microglia. J Neurosci Res 81(3): 403-11 (2005).
99. Xu J, Drew PD. 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. J Neuroimmunol 171(1-2): 135-44 (2006).
100. Dheen ST, Jun Y, Yan Z, Tay SS, Ling EA. Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia. Glia 50(1): 21-31 (2005).
101. Romieu-Mourez R, Coutu DL, Galipeau J. The immune plasticity of mesenchymal stromal cells from mice and men: concordances and discrepancies. Front Biosci 4: 824-37 (2012).
102. Rook GA. Immune responses to mycobacteria in mice and men. Proc Royal Soc Med 69(6): 442-4 (1976).
103. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol 172(5): 2731-8 (2004).
104. Kmonickova E, Melkusova P, Farghali H, Holy A, Zidek Z. Nitric oxide production in mouse and rat macrophages: a rapid and efficient assay for screening of drugs immunostimulatory effects in human cells. Nitric Oxide: biology and chemistry/official journal of the Nitric Oxide Society 17(3-4): 160-9 (2007).
105. Arias M, Zabaleta J, Rodriguez JI, Rojas M, Paris SC, Garcia LF. Failure to induce nitric oxide production by human monocytederived macrophages. Manipulation of biochemical pathways. Allergologia et immunopathologia 25(6): 280-8 (1997).
106. Reiling N, Ulmer AJ, Duchrow M, Ernst M, Flad HD, Hauschildt S. Nitric oxide synthase: mRNA expression of different isoforms in human monocytes/macrophages. Eur J Immunol 24(8): 1941-4 (1994).
107. Fang FC, Vazquez-Torres A. Nitric oxide production by human macrophages: there's NO doubt about it. Am J Physiol Lung Cell Mol Physiol 282(5): L941-3 (2002).
108. Steiner P, Efferen L, Durkin HG, Joseph GK, Nowakowski M. Nitric oxide production by human alveolar macrophages in pulmonary disease. Ann New York Acadf Sci 797: 246-9 (1996).
109. Ajmone-Cat MA, Mancini M, De Simone R, Cilli P, Minghetti L. Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures. Glia 61(10): 1698-711 (2013).
110. Vehmas AK, Kawas CH, Stewart WF, Troncoso JC. Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 24(2): 321-31 (2003).
111. Haga S, Akai K, Ishii T. Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody. Acta Neuropathologica 77(6): 569-75 (1989).
112. Ferretti MT, Cuello AC. Does a pro-inflammatory process precede Alzheimer's disease and mild cognitive impairment? CurrAlzheimer Res 8(2): 164-74 (2011).
113. Yanamadala V, Friedlander RM. Complement in neuroprotection and neurodegeneration. Trends Mol Med 16(2): 69-76 (2010).
114. van Beek J, Elward K, Gasque P. Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann New York Acad Sci 992: 56-71 (2003).
115. Yarchoan M, Louneva N, Xie SX, Swenson FJ, Hu W, Soares H, et al. Association of plasma C-reactive protein levels with the diagnosis of Alzheimer's disease. J Neurol Sci 333(1-2): 9-12 (2013).
116. Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V. Inflammatory process in Alzheimer's Disease. Front Integrat Neurosci 7: 59 (2013).
117. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer's disease, role of cytokines. Scientific World Journal 2012: 756357 (2012).
118. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 3(1): 23-35 (2003).
119. Franco R, Fernandez-Suarez D. Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131: 65-86 (2015).
120. Medeiros R, Kitazawa M, Passos GF, Baglietto-Vargas D, Cheng D, Cribbs DH, et al. Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice. Am J Pathol 182(5): 1780-9 (2013).
121. Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4: e525 (2013).
122. Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gammamediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 32(30): 10117-28 (2012).
123. Hjorth E, Zhu M, Toro VC, Vedin I, Palmblad J, Cederholm T, et al. Omega-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-beta42 by human microglia and decrease inflammatory markers. J Alzheimers Dis 35(4): 697-713 (2013).
124. Jha MK, Park DH, Kook H, Lee IK, Lee WH, Suk K. Metabolic Control of Glia-Mediated Neuroinflammation. Curr Alzheimer Res 13(4):387-402 (2016).
125. Tejera D, Heneka MT. Microglia in Alzheimer's disease: the good, the bad and the ugly. Curr Alzheimer Res 13(4):370-80 (2016).
126. Chan WY, Kohsaka S, Rezaie P. The origin and cell lineage of microglia: new concepts. Brain Res Rev 53(2): 344-54 (2007).
127. Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35(5): 601-12 (2013).
128. Kaindl AM, Ikonomidou C. Glutamate antagonists are neurotoxins for the developing brain. Neurotoxicity Res 11(3-4): 203-18 (2007).
129. Garrido-Mesa N, Zarzuelo A, Galvez J. Minocycline: far beyond an antibiotic. British J Pharmacol 169(2): 337-52 (2013).
130. Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflamm 9: 62 (2012).
131. Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger DP, Anderton BH. Minocycline reduces the development of abnormal tau species in models of Alzheimer's disease. FASEB J 23(3): 739-50 (2009).
132. Malm TM, Magga J, Kuh GF, Vatanen T, Koistinaho M, Koistinaho J. Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease. Glia 56(16): 1767-79 (2008).
133. Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology 32(11): 2393-404 (2007).