Pharmacological inhibition of PKR in APPswePS1dE9 mice transiently prevents inflammation at 12 months of age but increases Aß42 levels in the late stages of the Alzheimer's disease.
Curr Alzheimer Res
; 9(3): 344-60, 2012 Mar.
Article
em En
| MEDLINE
| ID: mdl-22272616
ABSTRACT
The double-stranded RNA-dependent protein kinase (PKR) is switched on by a wide range of stimuli, including the amyloid peptide. Then, PKR transmits signals to the translational machinery, apoptosis and inflammatory signaling pathways by interacting with some adapters. In virus-infected cells, PKR engages the nucleus factor κB (NF-κB) pathway. In many models of Alzheimer's disease (AD) and patients with AD, PKR was activated. Furthermore, there is strong evidence implicating the inflammatory process in the AD brain. However, the PKR involvement in inflammatory responses in AD is not elucidated. Based on our previous in vitro results, the aim of this study was to evaluate the effects of a pharmacological inhibition of PKR in inflammation in APPswePS1dE9 transgenic mice. Our results showed that PKR inhibition prevented the NF-κB activation and production of tumor necrosis factor alpha (TNFα) and interleukin (IL)-1ß at 12 months of age without decrease of Aß42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1ß- mediated inflammation and induced a great increase in ß-amyloid peptide (Aß42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and Aß42 levels. Moreover, the age-dependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Regulação para Cima
/
Peptídeos beta-Amiloides
/
EIF-2 Quinase
/
Doença de Alzheimer
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article