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
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↵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.