Microglial C5aR (CD88) expression correlates with amyloid-β deposition in murine models of Alzheimer's disease

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

Research output: Contribution to journalArticle

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Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-β protein and neuronal loss, is the leading cause of age-related dementia in the world today. The disease is also associated with neuroinflammation, robust activation of astrocytes and microglia, and evidence of activation of the complement system, localized with both fibrillar amyloid-β (fAβ) plaques and tangles. The observations are consistent with a complement-dependent component of AD progression. We have previously shown that inhibition of the major complement receptor for C5a (CD88) with the antagonist PMX205 results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of complement in AD-related neuroinflammation, we examined the age- and disease-associated expression of CD88 in brain of transgenic mouse models of AD and the influence of PMX205 on the presence of various complement activation products using flow cytometry, western blot, and immunohistochemistry. CD88 was found to be up-regulated in microglia, in the immediate vicinity of amyloid plaques. While thioflavine plaque load and glial recruitment is significantly reduced after treatment with PMX205, C1q remains co-localized with fAβ plaques and C3 is still expressed by the recruited astrocytes. Thus, with PMX205, potentially beneficial activities of these early complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific complement mediated activities as an approach for AD therapy.

Original languageEnglish (US)
Pages (from-to)389-401
Number of pages13
JournalJournal of Neurochemistry
Volume113
Issue number2
DOIs
StatePublished - Apr 1 2010

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Amyloid
Alzheimer Disease
Amyloid Plaques
Complement Activation
Microglia
Astrocytes
Chemical activation
Complement C5a
Amyloidogenic Proteins
Complement Receptors
Neurodegenerative diseases
Neuroglia
Neurodegenerative Diseases
Transgenic Mice
Dementia
Disease Progression
Flow cytometry
Flow Cytometry
Pathology
Western Blotting

Keywords

  • Alzheimer's Disease
  • C5a receptor
  • Complement
  • Microglia
  • Murine models
  • Neuroinflammation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Ager, R. R., Fonseca, M. I., Chu, S. H., Sanderson, S., Taylor, S. M., Woodruff, T. M., & Tenner, A. J. (2010). Microglial C5aR (CD88) expression correlates with amyloid-β deposition in murine models of Alzheimer's disease. Journal of Neurochemistry, 113(2), 389-401. https://doi.org/10.1111/j.1471-4159.2010.06595.x

Microglial C5aR (CD88) expression correlates with amyloid-β deposition in murine models of Alzheimer's disease. / Ager, Rahasson R.; Fonseca, Maria I.; Chu, Shu Hui; Sanderson, Sam; Taylor, Stephen M.; Woodruff, Trent M.; Tenner, Andrea J.

In: Journal of Neurochemistry, Vol. 113, No. 2, 01.04.2010, p. 389-401.

Research output: Contribution to journalArticle

Ager, RR, Fonseca, MI, Chu, SH, Sanderson, S, Taylor, SM, Woodruff, TM & Tenner, AJ 2010, 'Microglial C5aR (CD88) expression correlates with amyloid-β deposition in murine models of Alzheimer's disease', Journal of Neurochemistry, vol. 113, no. 2, pp. 389-401. https://doi.org/10.1111/j.1471-4159.2010.06595.x
Ager, Rahasson R. ; Fonseca, Maria I. ; Chu, Shu Hui ; Sanderson, Sam ; Taylor, Stephen M. ; Woodruff, Trent M. ; Tenner, Andrea J. / Microglial C5aR (CD88) expression correlates with amyloid-β deposition in murine models of Alzheimer's disease. In: Journal of Neurochemistry. 2010 ; Vol. 113, No. 2. pp. 389-401.
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