Pharmacological Inhibition of PKR in APPswePS1dE9 Mice Transiently Prevents Inflammation at 12 Months of Age but Increases Aβ42 Levels in the Late Stages of the Alzheimer’s Disease

Author(s): Julien Couturier , Marc Paccalin , Claire Lafay-Chebassier , Sylvie Chalon , Isabelle Ingrand , Jeremy Pinguet , Raymond Pontcharraud , Olivier Guillard , Bernard Fauconneau , Guylene Page .

Journal Name: Current Alzheimer Research

Volume 9 , Issue 3 , 2012

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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)-1β at 12 months of age without decrease of Aβ42 levels and memory deficits. Surprisingly, PKR inhibition failed to prevent IL-1β- mediated inflammation and induced a great increase in β-amyloid peptide (Aβ42) levels at 18 months of age. In this model, our findings highlight the lack of relationship between inflammation and Aβ42 levels. Moreover, the agedependent inflammatory response must be carefully taken into account in the establishment of an anti-inflammatory therapy in AD.

Keywords: PKR, NF-&kgr;B, inflammation, APPswePS1dE9, Aβ42 load, behavioral tests

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Article Details

VOLUME: 9
ISSUE: 3
Year: 2012
Page: [344 - 360]
Pages: 17
DOI: 10.2174/156720512800107582
Price: $58

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