QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (47) Citing Articles via Google Scholar Google Scholar Articles by Tan, J. Articles by Mullan, M. Search for Related Content PubMed PubMed Citation Articles by Tan, J. Articles by Mullan, M.

 Previous Article  |  Next Article 

The Journal of Neuroscience, October 15, 2000, 20(20):7587-7594

CD45 Opposes -Amyloid Peptide-Induced Microglial Activation via Inhibition of p44/42 Mitogen-Activated Protein Kinase

Jun Tan, Terrence Town, Takashi Mori, Yajuan Wu, Michael Saxe, Fiona Crawford, and Mike Mullan

The Roskamp Institute, Department of Psychiatry, University of South Florida, Tampa, Florida 33613

Reactive microglia have been suggested to play a role in the Alzheimer's disease (AD) process, and previous studies have shown that expression of CD45, a membrane-bound protein-tyrosine phosphatase (PTP), is elevated in microglia in AD brain compared with controls. To investigate the possible role of CD45 in microglial responsiveness to -amyloid (A) peptides, we first co-treated primary cultured microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1,10-phenanthroline) oxovanadate (phen), 5 µM] and freshly solubilized A peptides (1000 nM). Data show synergistic induction of microglial activation as evidenced by tumor necrosis factor  (TNF-) production and nitric oxide (NO) release, both of which we show to be dependent on activation of p44/42 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with phen and A peptides results in microglia-induced neuronal cell injury. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibits these effects via inhibition of p44/42 MAPK, suggesting that CD45 is a negative regulator of microglial activation. Accordingly, primary cultured microglia from CD45-deficient mice demonstrate hyper-responsiveness to A, as evidenced by TNF- release, NO production, and neuronal injury after stimulation with A peptides. As a validation of these findings in vivo, brains from a transgenic mouse model of AD [transgenic Swedish APP-overexpressing (Tg APP_sw) mice] deficient for CD45 demonstrate markedly increased production of TNF- compared with Tg APP_sw mice. Taken together, these results suggest that therapeutic agents that stimulate the CD45 PTP signaling pathway may be effective in suppressing microglial activation associated with AD.

Key words: Alzheimer's disease; -amyloid; microlgia; neurons; mitogen-activated protein kinase; CD45; protein-tyrosine phosphatase; tyrosine phospatase inhibitor; TNF-; nitric oxide

---

Copyright © 2000 Society for Neuroscience  0270-6474/00/20207587-08$05.00/0

This article has been cited by other articles:

				W. V. Nikolic, Y. Bai, D. Obregon, H. Hou, T. Mori, J. Zeng, J. Ehrhart, R. D. Shytle, B. Giunta, D. Morgan, et al. Transcutaneous beta-amyloid immunization reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage PNAS, February 13, 2007; 104(7): 2507 - 2512. [Abstract] [Full Text] [PDF]

				Q. Liu, J. Zhang, H. Zhu, C. Qin, Q. Chen, and B. Zhao Dissecting the signaling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model FASEB J, January 1, 2007; 21(1): 61 - 73. [Abstract] [Full Text] [PDF]

				D. F. Obregon, K. Rezai-Zadeh, Y. Bai, N. Sun, H. Hou, J. Ehrhart, J. Zeng, T. Mori, G. W. Arendash, D. Shytle, et al. ADAM10 Activation Is Required for Green Tea (-)-Epigallocatechin-3-gallate-induced {alpha}-Secretase Cleavage of Amyloid Precursor Protein J. Biol. Chem., June 16, 2006; 281(24): 16419 - 16427. [Abstract] [Full Text] [PDF]

				M. A. Cuadros, A. M. Santos, D. Martin-Oliva, R. Calvente, M. Tassi, J. L. Marin-Teva, and J. Navascues Specific Immunolabeling of Brain Macrophages and Microglial Cells in the Developing and Mature Chick Central Nervous System J. Histochem. Cytochem., June 1, 2006; 54(6): 727 - 738. [Abstract] [Full Text] [PDF]

				A. M. Floden and C. K. Combs Beta-amyloid stimulates murine postnatal and adult microglia cultures in a unique manner. J. Neurosci., April 26, 2006; 26(17): 4644 - 4648. [Abstract] [Full Text] [PDF]

				M.-O. Kim, H.-S. Suh, Q. Si, B. I. Terman, and S. C. Lee Anti-CD45RO Suppresses Human Immunodeficiency Virus Type 1 Replication in Microglia: Role of Hck Tyrosine Kinase and Implications for AIDS Dementia J. Virol., January 1, 2006; 80(1): 62 - 72. [Abstract] [Full Text] [PDF]

				Y. S. Kim, S. S. Kim, J. J. Cho, D. H. Choi, O. Hwang, D. H. Shin, H. S. Chun, M. F. Beal, and T. H. Joh Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia J. Neurosci., April 6, 2005; 25(14): 3701 - 3711. [Abstract] [Full Text] [PDF]

				A. M. Floden, S. Li, and C. K. Combs {beta}-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor {alpha} and NMDA Receptors J. Neurosci., March 9, 2005; 25(10): 2566 - 2575. [Abstract] [Full Text] [PDF]

				H.-S. Suh, M.-O. Kim, and S. C. Lee Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Signaling and Microglial Proliferation by Anti-CD45RO: Role of Hck Tyrosine Kinase and Phosphatidylinositol 3-Kinase/Akt J. Immunol., March 1, 2005; 174(5): 2712 - 2719. [Abstract] [Full Text] [PDF]

				B. G. Ramirez, C. Blazquez, T. G. del Pulgar, M. Guzman, and M. L. de Ceballos Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation J. Neurosci., February 23, 2005; 25(8): 1904 - 1913. [Abstract] [Full Text] [PDF]

				J. G. Richards, G. A. Higgins, A.-M. Ouagazzal, L. Ozmen, J. N. C. Kew, B. Bohrmann, P. Malherbe, M. Brockhaus, H. Loetscher, C. Czech, et al. PS2APP Transgenic Mice, Coexpressing hPS2mut and hAPPswe, Show Age-Related Cognitive Deficits Associated with Discrete Brain Amyloid Deposition and Inflammation J. Neurosci., October 1, 2003; 23(26): 8989 - 9003. [Abstract] [Full Text] [PDF]

				C. Zhou, A. Saxon, and K. Zhang Human Activation-Induced Cytidine Deaminase Is Induced by IL-4 and Negatively Regulated by CD45: Implication of CD45 as a Janus Kinase Phosphatase in Antibody Diversification J. Immunol., February 15, 2003; 170(4): 1887 - 1893. [Abstract] [Full Text] [PDF]

				T. Yamada, D. Zhu, A. Saxon, and K. Zhang CD45 Controls Interleukin-4-mediated IgE Class Switch Recombination in Human B Cells through Its Function as a Janus Kinase Phosphatase J. Biol. Chem., August 2, 2002; 277(32): 28830 - 28835. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help