| First Author | Fonseca MI | Year | 2009 |
| Journal | J Immunol | Volume | 183 |
| Issue | 2 | Pages | 1375-83 |
| PubMed ID | 19561098 | Mgi Jnum | J:151661 |
| Mgi Id | MGI:4354701 | Doi | 10.4049/jimmunol.0901005 |
| Citation | Fonseca MI, et al. (2009) Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol 183(2):1375-83 |
| abstractText | 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. |
