Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease.
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.
Fonseca
Maria I
MI
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
Ager
Rahasson R
RR
Chu
Shu-Hui
SH
Yazan
Ozkan
O
Sanderson
Sam D
SD
LaFerla
Frank M
FM
Taylor
Stephen M
SM
Woodruff
Trent M
TM
Tenner
Andrea J
AJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000517:prevention & control; D051379:Mice; D009410:Nerve Degeneration / Q000517:prevention & control*; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000473:pathology; D009457:Neuroglia / Q000473:pathology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010554:Personality Disorders / Q000517:prevention & control; D058225:Plaque, Amyloid / Q000187:drug effects / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*
D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; C504156:hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)