Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal ß-catenin pathway function in an Alzheimer's disease model.
J Immunol
; 187(12): 6539-49, 2011 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-22095718
ABSTRACT
Inflammation is a key pathological hallmark of Alzheimer's disease (AD), although its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, IL-1ß in particular has been implicated in playing a pathogenic role. In this study, we sought to investigate whether inhibition of IL-1ß signaling provides disease-modifying benefits in an AD mouse model and, if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1R blocking Ab significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-ß. Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3ß, and p38-MAPK, and also reduces phosphorylated tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/ß-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3ß activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas tau
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Transtornos Cognitivos
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Beta Catenina
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Interleucina-1beta
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Doença de Alzheimer
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Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article