Inflammation in Alzheimer disease: Driving force, bystander or beneficial response?

Nature Medicine

Volumn 12, Issue 9, 2006, Pages 1005-1015

  Wyss Coray, Tony ^a,b  

^a VA PALO ALTO HEALTH CARE SYSTEM   (United States)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; AMYLOID BETA PROTEIN; APOLIPOPROTEIN E; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MESSENGER RNA; NONSTEROID ANTIINFLAMMATORY AGENT; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA;

ALZHEIMER DISEASE; ASTROCYTE; CELL ACTIVATION; ENZYME LINKED IMMUNOSORBENT ASSAY; GENE EXPRESSION; GENETIC LINKAGE; GENETIC MANIPULATION; GENETIC POLYMORPHISM; HUMAN; IMMUNE SYSTEM; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; INFLAMMATION; MICROGLIA; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; REVIEW; TRANSGENICS;

EID: 33748471099     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: None     Document Type: Review

References (119)

1. Glenner, G.G. & Wong, C.W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885-890 (1984).
2. Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein Τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA 83, 4913-4917 (1986).
3. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706 (1991).
4. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754-760 (1995).
5. Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383-421 (2000).
6. Wyss-Coray, T. & Mucke, L. Inflammation in neurodegenerative disease: a double-edged sword. Neuron 35, 419-432 (2002).
7. Iqbal, K. et al. Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers. Ann. Neurol. 58, 748-757 (2005).
8. Eikelenboom, P. & Stam, F.C. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol. (Berl.) 57, 239-242 (1982).
9. McGeer, P.L., Itagaki, S., Boyes, B.E. & McGeer, E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285-1291 (1988).
10. Katsel, P.L., Davis, K.L. & Haroutunian, V. Large-scale microarray studies of gene expression in multiple regions of the brain in schizophrenia and Alzheimer's disease. Int. Rev. Neurobiol. 63, 41-82 (2005).
11. Blalock, E.M. et al. Harnessing the power of gene microarrays for the study of brain aging and Alzheimer's disease: statistical reliability and functional correlation. Ageing Res. Rev. 4, 481-512 (2005).
12. Colangelo, V. et al. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J. Neurosci. Res. 70, 462-473 (2002).
13. Groom, G.N., Junck, L., Foster, N.L., Frey, K.A. & Kuhl, D.E. PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer's disease. J. Nucl. Med. 36, 2207-2210 (1995).
14. Cagnin, A. et al. In-vivo measurement of activated microglia in dementia. Lancet 358, 461-467 (2001).
15. Versijpt, J.J. et al. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur. Neurol. 50, 39-47 (2003).
16. Mahley, R.W. & Rall, S.C., Jr. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507-537 (2000).
17. Mahley, R. & Huang, Y. Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond. Curr. Opin. Lipidol. 10, 207-217 (1999).
18. Lynch, J.R. et al. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J. Biol. Chem. 278, 48529-48533 (2003).
19. van den Elzen, P. et al. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437, 906-910 (2005).
20. Kanter, J.L. et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat. Med. 12, 138-143 (2006).
21. Chapman, J. et al. APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 56, 312-316 (2001).
22. McGeer, P.L., McGeer, E., Rogers, J. & Sibley, J. Anti-inflammatory drugs and Alzheimer disease. Lancet 335, 1037 (1990).
23. Rogers, J. et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 43, 1609-1611 (1993).
24. Scharf, S., Mander, A., Ugoni, A., Vajda, F. & Christophidis, V.N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 53, 197-201 (1999).
25. Hoozemans, J.J. & O'Banion, M.K. The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs. Curr. Drug Targets CNS Neurol. Disord. 4, 307-315 (2005).
26. Mackenzie, I.R.A. & Munoz, D.G. Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology 50, 986-990 (1998).
27. Lim, G.P. et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J. Neurosci. 20, 5709-5714 (2000).
28. Morgan, D., Gordon, M.N., Tan, J., Wilcock, D. & Rojiani, A.M. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. J. Neuropathol. Exp. Neurol. 64, 743-753 (2005).
29. Quinn, J. et al. Inflammation and cerebral amyloidosis are disconnected in an animal model of Alzheimer's disease. J. Neuroimmunol. 137, 32-41 (2003).
30. Lanz, T.A., Fici, G.J. & Merchant, K.M. Lack of specific amyloid-β(1-42) suppression by nonsteroidal anti-inflammatory drugs in young, plaque-free Tg2576 mice and in guinea pig neuronal cultures. J. Pharmacol. Exp. Ther. 312, 399-406 (2005).
31. Zhou, Y. et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302, 1215-1217 (2003).
32. Tegeder, I., Pfeilschifter, J. & Geisslinger, G. Cyclooxygenase- independent actions of cyclooxygenase inhibitors. FASEB J. 15, 2057-2072 (2001).
33. Eriksen, J.L. et al. NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo. J. Clin. Invest. 112, 440-449 (2003).
34. Sastre, M. et al. Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ. Proc. Natl. Acad. Sci. USA 103, 443-448 (2006).
35. Yan, Q. et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J. Neurosci. 23, 7504-7509 (2003).
36. Weggen, S. et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 414, 212-216 (2001).
37. Takahashi, Y. et al. Sulindac sulfide is a noncompetitive γ-secretase inhibitor that preferentially reduces Aβ42 generation. J. Biol. Chem. 278, 18664-18670 (2003).
38. Lleo, A. et al. Nonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation. Nat. Med. 10, 1065-1066 (2004).
39. Beher, D. et al. Selected non-steroidal anti-inflammatory drugs and their derivatives target γ-secretase at a novel site. Evidence for an allosteric mechanism. J. Biol. Chem. 279, 43419-43426 (2004).
40. Gasparini, L., Rusconi, L., Xu, H., del Soldato, P. & Ongini, E. Modulation of beta-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures. J. Neurochem. 88, 337-348 (2004).
41. Kukar, T. et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat. Med. 11, 545-550 (2005).
42. Wyss-Coray, T. Killing pain, killing neurons? Nat. Med. 11, 472-473 (2005).
43. Tegeder, I. et al. Inhibition of NF-κB and AP-1 activation by R- and S-flurbiprofen. FASEB J. 15, 595-597 (2001).
44. Sung, S. et al. Modulation of nuclear factor-κB activity by indomethacin influences Aβ levels but not Aβ precursor protein metabolism in a model of Alzheimer's disease. Am. J. Pathol. 165, 2197-2206 (2004).
45. Monsonego, A. & Weiner, H.L. Immunotherapeutic approaches to Alzheimer's disease. Science 302, 834-838 (2003).
46. Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523-527 (1995).
47. Hsia, A. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228-3233 (1999).
48. Masliah, E. et al. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer's disease. J. Neurosci. 16, 5795-5811 (1996).
49. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99-102 (1996).
50. Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402-405 (2000).
51. McGowan, E., Eriksen, J. & Hutton, M. A decade of modeling Alzheimer's disease in transgenic mice. Trends Genet. 22, 281-289 (2006).
52. Oddo, S. et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409-421 (2003).
53. Wu, Z.L. et al. Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. Neurobiol. Aging 27, 377-386 (2006).
54. Dickey, C.A. et al. Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J. Neurosci. 23, 5219-5226 (2003).
55. Reddy, P.H. et al. Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum. Mol. Genet. 13, 1225-1240 (2004).
56. Miller, R.J. & Tran, P.B. Chemokinetics. Neuron 47, 621-623 (2005).
57. Bellucci, A. et al. Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am. J. Pathol. 165, 1643-1652 (2004).
58. Ho, L. et al. Gene expression profiling of the tau mutant (P301L) transgenic mouse brain. Neurosci. Lett. 310, 1-4 (2001).
59. Heneka, M.T. et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J. Neuroinflammation [online] 2, 22 (2005) (doi:10.1186/1742-2094-2-22).
60. Nagasaka, Y. et al. A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings. Proc. Natl. Acad. Sci. USA 102, 14854-14859 (2005).
61. Andreasson, K.I. et al. Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J. Neurosci. 21, 8198-8209 (2001).
62. Xiang, Z. et al. Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology. Gene Expr. 10, 271-278 (2002).
63. Liang, X. et al. Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease. J. Neurosci. 25, 10180-10187 (2005).
64. Shie, F.S., Montine, K.S., Breyer, R.M. & Montine, T.J. Microglial EP2 as a new target to increase amyloid beta phagocytosis and decrease amyloid beta-induced damage to neurons. Brain Pathol. 15, 134-138 (2005).
65. Carroll, M.C. The role of complement and complement receptors in induction and regulation of immunity. Annu. Rev. Immunol. 16, 545-568 (1998).
66. Eikelenboom, P., Hack, C.E., Rozemuller, J.M. & Stam, F.C. Complement activation in amyloid plaques in Alzheimer's dementia. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 56, 259-262 (1989).
67. Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl. Acad. Sci. USA 99, 10837-10842 (2002).
68. Fonseca, M.I., Zhou, J., Botto, M. & Tenner, A.J. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J. Neurosci. 24, 6457-6465 (2004).
69. Wyss-Coray, T. et al. TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice. Nat. Med. 7, 612-618 (2001).
70. Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat. Med. 9, 453-457 (2003).
71. Wyss-Coray, T., Lin, C., Sanan, D., Mucke, L. & Masliah, E. Chronic overproduction of TGF-β1 in astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am. J. Pathol. 156, 139-150 (2000).
72. Brionne, T.C., Tesseur, I., Masliah, E. & Wyss-Coray, T. Loss of TGF-β1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40, 1133-1145 (2003).
73. Weller, R.O. et al. Cerebral amyloid angiopathy. Amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am. J. Pathol. 153, 725-733 (1998).
74. Tian, J., Shi, J., Bailey, K. & Mann, D.M. Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease. Neurosci. Lett. 352, 137-140 (2003).
75. Yamamoto, M. et al. Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. Am. J. Pathol. 166, 1475-1485 (2005).
76. Tan, J. et al. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat. Neurosci. 5, 1288-1293 (2002).
77. Wyss-Coray, T. et al. Key signaling pathways regulate the biological activities and accumulation of amyloid-β. Neurobiol. Aging 22, 967-973 (2001).
78. Arancio, O. et al. RAGE potentiates Aβ-induced perturbation of neuronal function in transgenic mice. EMBO J. 23, 4096-4105 (2004).
79. Abraham, C.R., Shirahama, T. & Potter, H. Alpha 1-antichymotrypsin is associated solely with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha 1-antichymotrypsin. Neurobiol. Aging 11, 123-129 (1990).
80. Nilsson, L.N. et al. α-1-Antichymotrypsin promotes β-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 21, 1444-1451 (2001).
81. 1- antichymotrypsin enhances Alzheimer-like pathology in amyloid protein precursor transgenic mice. Am. J. Pathol. 157, 2003-2010 (2000).
82. Craft, J.M., Watterson, D.M., Frautschy, S.A. & Van Eldik, L.J. Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol. Aging 25, 1283-1292 (2004).
83. Li, Y., Liu, L., Barger, S.W. & Griffin, W.S. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 23, 1605-1611 (2003).
84. Sheng, J.G., Zhu, S.G., Jones, R.A., Griffin, W.S.T. & Mrak, R.E. Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Exp. Neurol. 163, 388-391 (2000).
85. Kitazawa, M., Oddo, S., Yamasaki, T.R., Green, K.N. & LaFerla, F.M. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J. Neurosci. 25, 8843-8853 (2005).
86. Schneider, A. et al. Hyperphosphorylation and aggregation of tau in experimental autoimmune encephalomyelitis. J. Biol. Chem. 279, 55833-55839 (2004).
87. Wegiel, J. et al. Reduced number and altered morphology of microglial cells in colony stimulating factor-1-deficient osteopetrotic op/op mice. Brain Res. 804, 135-139 (1998).
88. Kaku, M. et al. Amyloid beta protein deposition and neuron loss in osteopetrotic (op/op) mice. Brain Res. Brain Res. Protoc. 12, 104-108 (2003).
89. Hickey, W.F. Basic principles of immunological surveillance of the normal central nervous system. Glia 36, 118-124 (2001).
90. Ono, K. et al. Migration of exogenous immature hematopoietic cells into adult mouse brain parenchyma under GFP-expressing bone marrow chimera. Biochem. Biophys. Res. Commun. 262, 610-614 (1999).
91. Beck, H. et al. Participation of bone marrow-derived cells in long-term repair processes after experimental stroke. J. Cereb. Blood Flow Metab. 23, 709-717 (2003).
92. Malm, T.M. et al. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol. Dis. 18, 134-142 (2005).
93. Stalder, A.K. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25, 11125-11132 (2005).
94. Simard, A.R., Soulet, D., Gowing, G., Julien, J.P. & Rivest, S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489-502 (2006).
95. Chiang, C.S., McBride, W.H. & Withers, H.R. Radiation-induced astrocytic and microglial responses in mouse brain. Radiother. Oncol. 29, 60-68 (1993).
96. Fiala, M., et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients. J. Alzheimers Dis. 7, 221-232; discussion 255-262 (2005).
97. Togo, T. et al. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J. Neuroimmunol. 124, 83-92 (2002).
98. Itagaki, S., McGeer, P.L. & Akiyama, H. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer's disease brain tissue. Neurosci. Lett. 91, 259-264 (1988).
99. Rogers, J., Luber-Narod, J., Styren, S.D. & Civin, W.H. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol. Aging 9, 339-349 (1988).
100. Skias, D., Bania, M., Reder, A.T., Luchins, D. & Antel, J.P. Senile dementia of Alzheimer's type (SDAT): reduced T8+-cell-mediated suppressor activity. Neurology 35, 1635-1638 (1985).
101. Pirttila, T., Mattinen, S. & Frey, H. The decrease of CD8-positive lymphocytes in Alzheimer's disease. J. Neurol. Sci. 107, 160-165 (1992).
102. Richartz-Salzburger, E., et al. Altered lymphocyte distribution in Alzheimer's disease. J. Psychiatr. Res. advance online publication, 3 March 2006 (doi:10.1016/j.jpsychir es.2006.01.010).
103. Dysken, M.W. et al. Distribution of peripheral lymphocytes in Alzheimer patients and controls. J. Psychiatr. Res. 26, 213-218 (1992).
104. Trieb, K., Ransmayr, G., Sgonc, R., Lassmann, H. & Grubeck-Loebenstein, B. APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer's disease. Neurobiol. Aging 17, 541-547 (1996).
105. Monsonego, A. et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J. Clin. Invest. 112, 415-422 (2003).
106. Nath, A. et al. Autoantibodies to amyloid beta-peptide (Aβ) are increased in Alzheimer's disease patients and Aβ antibodies can enhance Aβ neurotoxicity: implications for disease pathogenesis and vaccine development. Neuromolecular Med. 3, 29-39 (2003).
107. Weksler, M.E. et al. Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp. Gerontol. 37, 943-948 (2002).
108. Du, Y. et al. Reduced levels of amyloid β-peptide antibody in Alzheimer's disease. Neurology 57, 801-805 (2001).
109. Hyman, B.T. et al. Autoantibodies to amyloid-beta in Alzheimer's disease. Ann. Neurol. 49, 808-810 (2001).
110. Mruthinti, S. et al. Autoimmunity in Alzheimer's disease: increased levels of circulating IgGs binding Aβ and RAGE peptides. Neurobiol. Aging 25, 1023-1032 (2004).
111. Moir, R.D. et al. Autoantibodies to redox-modified oligomeric Aβ are attenuated in the plasma of Alzheimer's disease patients. J. Biol. Chem. 280, 17458-17463 (2005).
112. Eddleston, M. & Mucke, L. Molecular profile of reactive astrocytes-implications for their role in neurologic disease. Neuroscience 54, 15-36 (1993).
113. Mennicken, F., Maki, R., de Souza, E.B. & Quirion, R. Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol. Sci. 20, 73-78 (1999).
114. Gasque, P., Dean, Y.D., McGreal, E.P., Beek, J.V. & Morgan, B.P. Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49, 171-186 (2000).
115. Warner, T.D. & Mitchell, J.A. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 18, 790-804 (2004).
116. Lehmann, J.M., Lenhard, J.M., Oliver, B.B., Ringold, G.M. & Kliewer, S.A. Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 272, 3406-3410 (1997).
117. Bernardo, A., Ajmone-Cat, M.A., Gasparini, L., Ongini, E. & Minghetti, L. Nuclear receptor peroxisome proliferator-activated receptor-γ is activated in rat microglial cells by the anti-inflammatory drug HCT1026, a derivative of flurbiprofen. J. Neurochem. 92, 895-903 (2005).
118. Stellwagen, D. & Malenka, R.C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054-1059 (2006).
119. Wahl, S.M. Transforming growth factor beta (TGF-β) in inflammation: a cause and a cure. J. Clin. Immunol. 12, 61-74 (1992).