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

Maria I. Fonseca, Rahasson R. Ager, Shu Hui Chu, Ozkan Yazan, Sam Sanderson, Frank M. LaFerla, Stephen M. Taylor, Trent M. Woodruff, Andrea J. Tenner

Research output: Contribution to journalArticle

137 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1375-1383
Number of pages9
JournalJournal of Immunology
Volume183
Issue number2
DOIs
StatePublished - Jul 15 2009

Fingerprint

Alzheimer Disease
Pathology
Amyloid Plaques
Anaphylatoxin C5a Receptor
Therapeutics
Neurofibrillary Tangles
Complement Activation
Brain
Microglia
GTP-Binding Proteins
Neuroglia
Astrocytes
Cognition
Dementia
Disease Progression
Rodentia
Inflammation
hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)

ASJC Scopus subject areas

  • Immunology

Cite this

Fonseca, M. I., Ager, R. R., Chu, S. H., Yazan, O., Sanderson, S., LaFerla, F. M., ... Tenner, A. 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. https://doi.org/10.4049/jimmunol.0901005

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; LaFerla, Frank M.; Taylor, Stephen M.; Woodruff, Trent M.; Tenner, Andrea J.

In: Journal of Immunology, Vol. 183, No. 2, 15.07.2009, p. 1375-1383.

Research output: Contribution to journalArticle

Fonseca, MI, Ager, RR, Chu, SH, Yazan, O, Sanderson, S, LaFerla, FM, Taylor, SM, Woodruff, TM & Tenner, AJ 2009, 'Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease', Journal of Immunology, vol. 183, no. 2, pp. 1375-1383. https://doi.org/10.4049/jimmunol.0901005
Fonseca, Maria I. ; Ager, Rahasson R. ; Chu, Shu Hui ; Yazan, Ozkan ; Sanderson, Sam ; LaFerla, Frank M. ; Taylor, Stephen M. ; Woodruff, Trent M. ; Tenner, Andrea J. / Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. In: Journal of Immunology. 2009 ; Vol. 183, No. 2. pp. 1375-1383.
@article{ef01014345d6404cb43cd26f5fdc1096,
title = "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.",
author = "Fonseca, {Maria I.} and Ager, {Rahasson R.} and Chu, {Shu Hui} and Ozkan Yazan and Sam Sanderson and LaFerla, {Frank M.} and Taylor, {Stephen M.} and Woodruff, {Trent M.} and Tenner, {Andrea J.}",
year = "2009",
month = "7",
day = "15",
doi = "10.4049/jimmunol.0901005",
language = "English (US)",
volume = "183",
pages = "1375--1383",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "2",

}

TY - JOUR

T1 - Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease

AU - Fonseca, Maria I.

AU - Ager, Rahasson R.

AU - Chu, Shu Hui

AU - Yazan, Ozkan

AU - Sanderson, Sam

AU - LaFerla, Frank M.

AU - Taylor, Stephen M.

AU - Woodruff, Trent M.

AU - Tenner, Andrea J.

PY - 2009/7/15

Y1 - 2009/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=69249152289&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69249152289&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0901005

DO - 10.4049/jimmunol.0901005

M3 - Article

VL - 183

SP - 1375

EP - 1383

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -