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

Fonseca, Maria I., Ager, Rahasson R., Chu, Shu-Hui, Yazan, Ozkan, Sanderson, Sam D., LaFerla, Frank M., Taylor, Stephen M., Woodruff, Trent M. and Tenner, Andrea 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. doi:10.4049/jimmunol.0901005


Author Fonseca, Maria I.
Ager, Rahasson R.
Chu, Shu-Hui
Yazan, Ozkan
Sanderson, Sam D.
LaFerla, Frank M.
Taylor, Stephen M.
Woodruff, Trent M.
Tenner, Andrea J.
Title Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2009-07-15
Year available 2009
Sub-type Article (original research)
DOI 10.4049/jimmunol.0901005
Open Access Status DOI
Volume 183
Issue 2
Start page 1375
End page 1383
Total pages 9
Place of publication Bethesda, MD, United States
Publisher American Association of Immunologists
Language eng
Subject 06 Biological Sciences
11 Medical and Health Sciences
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. The Journal of Immunology, 2009, 183: 1375-1383.
Formatted 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.
Keyword Complement factor 5A
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID NS 35144
455856
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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