Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease.

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.

• Authors: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 2 Pg. 1375-83 (Jul 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19561098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides, Cyclic
• Receptor, Anaphylatoxin C5a
• Receptors, Complement
• hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)

Topics

• Alzheimer Disease (drug therapy, pathology, physiopathology)
• Animals
• Disease Models, Animal
• Inflammation (prevention & control)
• Mice
• Nerve Degeneration (prevention & control)
• Neurofibrillary Tangles (drug effects, pathology)
• Neuroglia (pathology)
• Peptides, Cyclic (administration & dosage, pharmacology, therapeutic use)
• Personality Disorders (prevention & control)
• Plaque, Amyloid (drug effects, pathology)
• Receptor, Anaphylatoxin C5a (antagonists & inhibitors)
• Receptors, Complement (antagonists & inhibitors)