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Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease

Maria I. Fonseca, Rahasson R. Ager, Shu-Hui Chu, Ozkan Yazan, Sam D. Sanderson, Frank M. LaFerla, Stephen M. Taylor, Trent M. Woodruff and Andrea J. Tenner
J Immunol July 15, 2009, 183 (2) 1375-1383; DOI: https://doi.org/10.4049/jimmunol.0901005
Maria I. Fonseca
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Rahasson R. Ager
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Shu-Hui Chu
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Ozkan Yazan
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Sam D. Sanderson
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Frank M. LaFerla
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Stephen M. Taylor
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Trent M. Woodruff
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Andrea J. Tenner
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Abstract

Alzheimer’s disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2–3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49–62%) and activated glia (42–68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵1 This research was supported by National Institutes of Health Grants NS 35144 (to A.J.T.) and P50 AG-00538, National Institutes of Health Training Grant NS-007444 (to R.R.A.), and a Project Grant from the National Health and Medical Research Council of Australia (Grant 455856 to S.M.T.).

  • ↵2 Address correspondence and reprint requests to Dr. Andrea J. Tenner, Department of Molecular Biology and Biochemistry, University of California, Irvine, 3205 McGaugh Hall, Irvine, CA 92697. E-mail address: atenner{at}uci.edu

  • Received March 30, 2009.
  • Accepted May 14, 2009.
  • Copyright © 2009 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 183 (2)
The Journal of Immunology
Vol. 183, Issue 2
15 Jul 2009
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Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease
Maria I. Fonseca, Rahasson R. Ager, Shu-Hui Chu, Ozkan Yazan, Sam D. Sanderson, Frank M. LaFerla, Stephen M. Taylor, Trent M. Woodruff, Andrea J. Tenner
The Journal of Immunology July 15, 2009, 183 (2) 1375-1383; DOI: 10.4049/jimmunol.0901005

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Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease
Maria I. Fonseca, Rahasson R. Ager, Shu-Hui Chu, Ozkan Yazan, Sam D. Sanderson, Frank M. LaFerla, Stephen M. Taylor, Trent M. Woodruff, Andrea J. Tenner
The Journal of Immunology July 15, 2009, 183 (2) 1375-1383; DOI: 10.4049/jimmunol.0901005
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