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

Research output: Contribution to journalArticle

145 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1375-1383
Number of pages9
JournalJournal of Immunology
Volume183
Issue number2
DOIs
StatePublished - Jul 15 2009
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Fonseca, M. I., Ager, R. R., Chu, S. H., Yazan, O., Sanderson, S. D., LaFerla, F. M., Taylor, S. M., Woodruff, T. M., & Tenner, A. J. (2009). Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. Journal of Immunology, 183(2), 1375-1383. https://doi.org/10.4049/jimmunol.0901005