D. ROS production and neuronal damage in the cerebral cortex of APP/PS1
Ⅴ. CONCLUSION
This study showed that the activated microglia surrounding plaques induced excessive expression of pro-inflammatory mediators such as IL-1β, TNF-α, iNOS and ROS, leading to neuronal damage in the cerebral cortex of APP/PS1 mice. Our previous study demonstrated that LPS-induced endogenous expression of IL-10 in microglia down-regulated brain inflammation and neuronal damage in the rat cerebral cortex. However, in the present study, we did not find of an association between IL-10 expression and down-regulation of brain inflammation. Therefore, further understanding the mechanisms of IL-10 expression in chronic brain inflammation may be an important point to comprehend the pathogenesis of Alzheimer’s disease.
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REFERENCES
1. Abramov AY, Scorziello A, Duchen MR: Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation.
J Neurosci 27: 1129-1138, 2007
2. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383-421, 2000
3. Alpar A, Ueberham U, Bruckner MK, Seeger G, Arendt T, Gartner U: Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice. Brain Res 1099: 189-198, 2006
4. Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA, Brooker G, Mocchetti I: Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21: 3104-3112, 2001
26
5. Banati RB, Gehrmann J, Schubert P, Kreutzgerg GW: Cytotoxicity of microglia. Glia 7: 111-118, 1993
6. Bethea JR, Nagashima H, Acosta MC, Briceno C, Gomez F, Marcillo AE, Loor K, Green J, Dietrich WD: Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 16: 851-863, 1999
7. Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B: TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. Faseb J 13: 63-68, 1999
8. Bogdan C, Paik J, Vodovotz Y, Nathan C: Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 267: 23301-23308, 1992
9. Boje KM, Arora PK: Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587: 250-256, 1992
10. Bornemann KD, Wiederhold KH, Pauli C, Ermini F, Stalder M, Schnell L, Sommer B, Jucker M, Staufenbiel M: Aβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice. Am J Pathol 158: 63-73, 2001
27
11. Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK: Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 149: 2736-2741, 1992
12. Chao CC, Hu S, Peterson PK: Glia, cytokines, and neurotoxicity. Crit Rev Neurobiol 9: 189-205, 1995
13. Dawson VL, Brahmbhatt HP, Mong JA, Dawson TM: Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. Neuropharmacology 33: 1425-1430, 1994
14. Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C: Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. Glia 7:
75-83, 1993
15. Dietrich WD, Busto R, Bethea JR: Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischemia in rats. Exp Neurol 158: 444-450, 1999
16. Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC, Vinters HV:
Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur J Clin Invest 32: 360-371, 2002
28
17. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, Bernard G: Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients. J Alzheimers Dis 7(3): 221-232; discussion 255-262, 2005
18. Fiorentino DF, Zlontnik A, Mossman TR, Howard M O’Garra A: IL-10 inhibits cytokine production by activated macrophages. J Immunol 147: 3815–3822, 1991
19. Gebicke-Haerter PJ, Spleiss O, Ren LQ, Li H, Dichmann S, Norgauer J, Boddeke HW: Microglial chemokines and chemokine receptors. Prog Brain Res 132: 525-532, 2001
20. Glezer I, Simard AR, Rivest S: Neuroprotective role of the innate immune system by microglia. Neuroscience 147: 867-883, 2007
21. Gonzalez-Scarano F, Baltuch G: Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 22: 219-240, 1999
22. Goodwin JL, Uemura E, Cunnick JE: Microglial release of nitric oxide by the synergistic action of beta-amyloid and IFN-gamma. Brain Res 692: 207-214, 1995
23. Grilli M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, Ongini E:
Interleukin-29
10modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci 12: 2265-2272, 2000
24. Haas J, Storch-Hagenlocher B, Biessmann A, Wildemann B: Inducible nitric oxide synthase and argininosuccinate synthetase: co-induction in brain tissue of patients with Alzheimer's dementia and following stimulation with beta-amyloid 1-42 in vitro.
Neurosci Lett 322: 121-5, 2002
25. Ii M, Sunamoto M, Ohnishi K, Ichimori Y: beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. Brain Res 720: 93-100, 1996
26. Jankowsky JL, Slun HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR: APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1.
Neurobiol Aging 25: 885-892, 2004
27. Klegeris A, Walker DG, McGeer PL: Activation of macrophages by Alzheimer beta amyloid peptide. Biochem Biophys Res Commun 199: 984-991, 1994
28. Klegeris A, McGeer PL: beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate. J Neurosci Res 49: 229-235, 1997
30
29. Koshinaga M, Katayama Y, Fukushima M, Oshima H, Suma T, Takahata T: Rapid and widespread microglial activation induced by traumatic brain injury in rat brain slices.
J Neurotrauma 17: 185-192, 2000
30. Kremlev SG, Palmer C: Interleukin-10 inhibits endotoxin-induced proinflammatory cytokines in microglial cell cultures. J Neuroimmunol 162: 71-80, 2005
31. Lee HG, Park KW, Jin BK, Lee YB: Interleukin-10 endogenously expressed in microglia prevents lipopolysaccharide-induced neurodegeneration in the rat cerebral cortex in vivo. Exp Mol Med 39: 812-819, 2007
32. Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS: Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 279: 49523-49532, 2004
33. Mallat M, Chamak B: Brain macrophages: neurotoxic or neurotrophic effector cells?
J Leukoc Biol 56: 416-422, 1994
34. Martino G: How the brain repairs itself: new therapeutic strategies in inflammatory and degenerative CNS disorders. Lancet Neurol 3: 372-378, 2004
31
35. McGeer PL, McGeer EG: Inflammation, autotoxicity and Alzheimer disease.
Neurobiol Aging 22: 799-809, 2001
36. Meda L, Cassatella MA, Szendrei GI, Otvos L, Jr, Baron P, Villalba M, Ferrari D, Rossi F: Activation of microglial cells by beta-amyloid protein and interferon-gamma.
Nature 374: 647-650, 1995
37. Mizuno T, Sawada M, Marunouchi T, Suzumura A: Production of IL-10 by mouse glial cells in culture. Biochem Biophys Res Comm 205: 1907-1915, 1994
38. Molina-Holgado E, Vela JM, Arevalo-Martin A, Guaza C: LPS/IFN-gamma cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the anti-inflammatory cytokine IL-10. Eur J Neurosci 13: 493-502, 2001
39. Morgan JH, Gamblin TC, Adkins JR, Groves JR, Dalton ML, Ashley DW:
Norepinephrine is a more potent inhibitor of tumor necrosis factor over a range of doses than dopamine. Am Surg 70: 526-528, 2004
40. Mrak RE, Griffin WS: Interleukin-1 and the immunogenetics of Alzheimer disease. J Neuropathol Exp Neurol 59: 471-476, 2000
41. Nguyen MD, Julien JP, Rivest S: Innate immunity: the missing link in neuroprotection
32
and neurodegeneration? Nat Rev Neurosci 3: 216-227, 2002
42. Perry VH, Bolton SJ, Anthony DC, Betmouni S: The contribution of inflammation to acute and chronic neurodegeneration. Res Immunol 149: 721-725, 1998
43. Piani D, Frei K, Do KQ, Cuenod M, Fontana A: Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci Lett 133: 159-162, 1991
44. Piani D, Spranger M, Frei K, Schaffner A, Fontana A: Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol 22: 2429-2436, 1992
45. Polazzi E, Gianni T, Contestabile A: Microglial cells protect cerebellar granule neurons from apoptosis: evidence for reciprocal signaling. Glia 36: 271-280, 2001
46. Remarque EJ, Bollen EL, Weverling-Rijnsburger AW, Laterveer JC, Blauw GJ, Westendorp RG: atients with Alzheimer's disease display a pro-inflammatory phenotype. Exp Gerontol 36: 171-176, 2001
47. Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH,
33
Brachova L, Bradt B, Ward P: Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 89: 10016-10020, 1992
48. Rosales-Corral S, Tan DX, Reiter RJ, Valdivia-Velazquez M, Acosta-Martinez JP, Ortiz GG: Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-beta onto the hippocampus in vivo. J Neuroimmunol 150: 20-28, 2004
49. Ryu JK, Kim J, Choi SH, Oh YJ, Lee YB, Kim SU, Jin BK: ATP-induced in vivo neurotoxicity in the rat striatum via P2 receptors. Neuroreport 13: 1611-1615, 2002
50. Sawada M, Suzumura A, Hosoya H, Marunouchi T, Nagatsu T: Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. J Neurochem 72: 1466-1471, 1999
51. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173-177, 1999
52. Selkoe DJ, Schenk D: Alzheimer's disease: molecular understanding predicts
34
amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43: 545-584, 2003
53. Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B: Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer's disease patients. Lab Invest 66: 223-230, 1992
54. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW: Interleukin-10 in the brain. Crit Rev Immunol 21: 427-449, 2001
55. 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: 49-62, 2001
56. Thery C, Chamak B, Mallat M: Cytotoxic Effect of Brain Macrophages on Developing. Eur J Neurosci 3: 1155-1164, 1991
57. Tsunawaki S, Sporn M, Ding A, Nathan CF: Deactivation of macrophages by transforming growth factor β. Nature 334: 260–262, 1988
58. Van der Wal EA, Gomez-Pinilla F, Cotman CW: Transforming growth factor-beta 1 is in plaques in Alzheimer and down pathologies. Neuroreport 4: 69-72, 1993
35
59. Van Muiswinkel FL, Veerhuis R, Eikelenboom P: Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem 66: 2468-2476, 1996
60. Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, Tieu K, Przedborski S: The role of glial cells in Parkinson's disease. Curr Opin Neurol 14:
483-489, 2001
61. Wang L, Goillot E, Tepper RI: IL-10 inhibits alloreactive cytotoxic T lymphocyte generation in vivo. Cell Immunol 159: 152-169, 1994
62. Wilkinson BL, Landreth GE: The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease. J Neuroinflammation 3: 30, 2006
63. Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S: NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc Natl Acad Sci U S A 100: 6145-6150, 2003
64. Xia MQ, Hyman BT: Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease. J Neurovirol 5: 32-41, 1999
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- 국문요약 -
현이 Iba1-면역양성을 보이는 마이크로글리아에서 대부분 배치됨을 관찰하였 다. 활성산소종 (ROS) 생성은 8개월부터 나타나며 14개월과 17개월 사이에서 두드러지게 증가되었다. NADPH oxidase의 주요 구성물질인 gp91phox 단백질 은 Iba1-면역양성을 보이는 마이크로글리아에서 대부분 배치됨을 관찰하였다.
또한, 14개월과 17개월의 대뇌피질에서 NeuN-양성적 뉴론과 MAP2-면역반 응적인 수지상 돌기가 상당히 감소되어 있음을 관찰하였다. 이 결과들은 알츠 하이머병 뇌조직에서 섬유성 아밀로이드 베타 (fibrillar β-amyloid)의 축적에 따라, 활성화된 마이크로글리아가 염증성 매개물질의 과도한 발현과 NADPH oxidase 활성화에 의한 활성산소종 생성을 유도하여 뉴론의 손상을 야기시킬 수 있음을 보여준다.
핵심어: 알츠하이머 질병, 인터루킨-10, 마이크로글리아, IL-1β, TNF-α, iNOS, 활성산소종
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