Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's disease.
J Neurochem
; 113(2): 389-401, 2010 Apr.
Article
em En
| MEDLINE
| ID: mdl-20132482
ABSTRACT
Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta 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-beta (fAbeta) 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 fAbeta 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
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Estatística como Assunto
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Peptídeos beta-Amiloides
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Microglia
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Receptor da Anafilatoxina C5a
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Doença de Alzheimer
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos