Top

Published in:

01-12-2003 | Regular Paper

Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains

Authors: Kazuhiro Imamura, Nozomi Hishikawa, Makoto Sawada, Toshiharu Nagatsu, Mari Yoshida, Yoshio Hashizume

Published in: Acta Neuropathologica | Issue 6/2003

Abstract

There are numerous observations confirming that microglia expressing major histocompatibility complex (MHC) class II molecules are associated with the central nervous system (CNS) in aging and pathological conditions. In this study, we investigated the distribution of MHC class II-positive microglia in Parkinson's disease (PD) brains. The number of MHC class II-positive microglia in the substantia nigra (SN) and putamen increased as the neuronal degeneration of the SN proceeded. These cells were also ICAM-1 (CD54) and LFA-1 (CD11a) positive. The number of activated microglia not only in the SN and putamen but also in the hippocampus, transentorhinal cortex, cingulate cortex and temporal cortex in PD was significantly higher than that in the normal control. Most activated microglia persisted regardless of the presence or absence of Lewy bodies. They were frequently associated not only with α-synuclein-positive Lewy neurites, but also with TH-16-positive dopaminergic and WH-3-positive serotonergic neurites, as well as MAP-2- and SMI-32-positive neurites. These activated microglia were also positive for TNF-α and interleukin-6, which are known to have a neuroprotective function. We conclude that MHC class II-positive microglia are a sensitive index of neuropathological change and are actively associated with damaged neurons and neurites.

Akiyama H, Kawamura T, Yamada T, Tooyama I, Ishii T, McGeer PL (1993) Expression of intercellular adhesion molecule (ICAM-1) by a subset of astrocytes in Alzheimer disease and some other degenerative neurological disorders. Acta Neuropathol 85:628–634PubMed

Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289

Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP (1995) Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a kB-binding factor and attenuation of peroxide and Ca²⁺ accumulation. Proc Natl Acad Sci USA 92:9328–9332

Batchelor PE, Liberatore GT, Wong JYF, Porritt MJ, Frerichs F, Donnan GA, Howells DH (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19:1708–1716PubMed

Bevezovskaya O, Maysinger D, Fedoroff S (1995) The hemapoietic cytokine, colony stimulating factor 1, is also a growth factor in the CNS: congenital absence of CSF-1 in mice results in abnormal microglial response and increased neuron vulnerability to injury. Int J Dev Neurosci 13:285–299CrossRefPubMed

Braak H, Braak E, Yilmazer D, Vos RAI, Jansen ENH, Bohl J, Jellinger K (1994) Amygdala pathology in Parkinson's disease. Acta Neuropathol 88:493–500CrossRefPubMed

Brown H, Kozlowski R, Perry VH (1998) The importance of ion channels for macrophage and microglia activation in vitro. Glia 22:94–97CrossRefPubMed

Bruce-Keller AJ (1999) Microglial-neuronal interactins in synaptic damage and recovery. J Neurosci Res 58:191–201CrossRefPubMed

Cai TQ, Wright SD (1995) Energetics of leukocyte integrin activation. J Biol Chem 270:14358–14365CrossRefPubMed

10.

Cassarino DS, Fall CP, Swerdlow RH, Smith TS, Halvorsen EM, Miller SW, Parks JP, Parker WD Jr, Bennett JP Jr (1997) Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease. Biochim Biophys Acta 1362:77–86CrossRefPubMed

11.

Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 149:2736–2741PubMed

12.

Cheng B, Mattson M (1994) Tumor necrosis factors protect neurons against excitotoxic /metabolic insults and promote maintenance of calcium homeostasis. Neuron 12:139–153

13.

Dickson DW, Mattiace LA, Kure K, Hutchins K, Lyman WD, Brosman CF (1991) Microglia in human disease with an emphasis on acquired immune deficiency syndrome. Lab Invest 64:135–156PubMed

14.

Gai WP, Blessing WW, Blumbergs PC (1995) Ubiquitin-positive degenerating neurites in the brainstem in Parkinson's disease. Brain 118:1447–1459PubMed

15.

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 27:119–137CrossRefPubMed

16.

Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-prignot A, Turmel H, Srinivasan A, Ruberg M, Evan GL, Agid Y, Hirsch EC (2000) Caspase-3: a vulnerability factor and a final effector in the apoptotic cell death of dopaminergic neurons in Parkinson's disease. Proc Natl Acad Sci USA 97:2875–2880PubMed

17.

Hartmann A, Troadec JD, Hunot S, Kikly K, Faucheux BA, Mouatt-Prigent A, Ruberg M, Agid Y, Hirsch EC (2001) Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J Neurosci 21:2247–2255PubMed

18.

Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292PubMed

19.

Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, Hirsch EC (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72:355–363CrossRefPubMed

20.

Imamura K, Ito M, Suzumura A, Asai J, Takahashi A (1990) Generation and characterization of monoclonal antibodies against rat microglia and ontogenic distribution of positive cells. Lab Invest 63:853–861PubMed

21.

Isaksson J, Farooque M, Holtz A, Hillered L, Olsson Y (1999) Expression of ICAM-1 and CD11b after experimental spinal cord injury in rats. J Neurotrauma 16:165–173PubMed

22.

Iseki E, Kato M, Marui W, Ueda K, Kosaka K (2001) A neuropathological study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies. J Neurol Sci 185:129–134PubMed

23.

Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D (1989) Relationship of microglia in and around senile (neuritic) plaques in Alzheimer brain. J Neuroimmunol 24:173–182PubMed

24.

Jellinger KA (2000) Cell death mechanism in Parkinson's disease. J Neural Transm 107:1–29CrossRefPubMed

25.

Kettenmann H, Hoppe D, Gottmann K, Bannati R, Kreutzberg G (1990) Cultured microglial cells have a distinct pattern of membrane channels different from peritoneal macrophages. J Neurosci Res 26:278–287PubMed

26.

Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20:6309–6316PubMed

27.

Koutsilieri E, Scheller C, Grünblatt E, Nara K, Li J, Riederer P (2002) Free radicals in Parkinson's disease. J Neurol 249 (Suppl 2):II/1–II/5

28.

Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMed

29.

Lazarov-Spiegler O, Soloman AS, Zeev-Brann AB, Hirschberg DL, Lavie V, Schwartz M (1996) Transplantation of activated macrophages overcomes central nervous system regrowth failure. FASEB J 10:1296–1302PubMed

30.

Liu B, Du L, Hong JS (2000) Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther 293:607–617

31.

Mackenzie IRA (2000)Activated microglia in dementia with Lewy bodies. Neurology 55:132–134PubMed

32.

Mattiace LA, Davies P, Dickson DW (1990) Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. Am J Pathol 136:1101–1114

33.

McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200CrossRefPubMed

34.

McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Expression of HLA-DR and interleukin-2 receptors on reactive microglia in senile dementia of Alzheimer type. J Neuroimmunol 16:122CrossRef

35.

McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38:1285–1291PubMed

36.

McGeer PL, Itagaki S, Tago H, McGeer EG (1988) Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76:550–557PubMed

37.

McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG (1993) Microglia in degenerative neurological disease. Glia 7:84–92PubMed

38.

McGuire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey PM (2001) Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons. Exp Neurol 169:219–230CrossRefPubMed

39.

McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon, DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen ENH, Ballard C, Vos RA de, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124PubMed

40.

Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammation process in Parkinson's disease. Neuroscience 95:425–432CrossRefPubMed

41.

Moller JC, Klein MA, Haas S, Jones LL, Kreutzberg GW, Raivich G (1996) Regulation of thrombospondin in the regenerating mouse facial nucleus. Glia 17:121–132CrossRefPubMed

42.

Nagata K, Nakajima K, Kohsaka K (1993) Plasminogen promotes the development of rat mesencephalic dopaminergic neurons in vitro. Dev Brain Res 75:31–37CrossRef

43.

Nagatsu T, Mogi M, Ichinose H, Togari A, Riederor P (1999) Cytokines in Parkinson's disease. Neuro Sci News 2:88–90

44.

Perry VH (1998) A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J Neuroimmunol 90:113–121CrossRef

45.

Perry VH, Hume DA, Gordon S (1985) Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15:313–326CrossRefPubMed

46.

Prewitt LM, Niesmann IR, Kane CJM, Houle JD (1997) Activated macrophage/microglial cells can promote the regeneration of sensory axons into the injured spinal cord. Exp Neurol 148:433–443CrossRefPubMed

47.

Rabchevsky AG, Streit WJ (1997) Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res 47:34–48CrossRefPubMed

48.

Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease. Neurobiol Aging 9:339–349PubMed

49.

Rozemuller JM, Eikelenboom P, Stam FC, Beyreuther K, Masters CL (1989) A4 protein in AD: primary and secondary cellular events in extracellular amyloid deposits. J Neuropathol Exp Neurol 48:647–663

50.

Sawada M, Suzumura A, Marunouchi T (1995) Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci 13:253–264CrossRefPubMed

51.

Styren SD, Civin WH, Rogers J (1990) Molecular, cellular and pathologic characterization of HLA-DR immunoreactivity in normal elderly and Alzheimer's disease brain. Exp Neurol 110:93–104PubMed

52.

Sudo S, Tanaka J, Toku K, Desaki J, Matsuda S, Arai T, Sakanaka M, Maeda N (1998) Neurons induce the activation of microglial cells in vitro. Exp Neurol 154:499–510CrossRefPubMed

53.

Toku K, Tanaka J, Yano H, Desaki J, Zhang B, Yang L, Ishihara K, Sakanaka M, Maeda N (1998) Microglial cells prevent nitric oxide-induced neuronal apoptosis in vitro. J Neurosci Res 53:415–425CrossRefPubMed

54.

Upender MB, Naegele JR (1999) Activation of microglia during developmentally regulated cell death in the cerebral cortex. Rev Neurosci 21:491–505CrossRef

55.

Werner A, Kloss CUA, Walter J, Kreutzberg GW, Raivich G (1998) Intercellular adhesion molecule-1 (ICAM-1) in the mouse facial motor nucleus after axonal injury and during regeneration. J Neurocytol 27:219–232

Title: Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains
Authors: Kazuhiro Imamura
Nozomi Hishikawa
Makoto Sawada
Toshiharu Nagatsu
Mari Yoshida
Yoshio Hashizume
Publication date: 01-12-2003
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 6/2003
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-003-0766-2

At a glance: The STEP trials

Springer Medicine

Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2003

Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families

Hyperproliferation of synapses on spinal motor neurons of Duchenne muscular dystrophy and myotonic dystrophy patients

α-Synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study

Intracranial extramedullary hematopoiesis associated with pilocytic astrocytoma: a case report

Oxidative damage in the olfactory system in Alzheimer's disease

CADASIL: new cases and new questions