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
Current Alzheimer Research
Title: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
Volume: 9 Issue: 3
Author(s): Julien Couturier, Marc Paccalin, Claire Lafay-Chebassier, Sylvie Chalon, Isabelle Ingrand, Jeremy Pinguet, Raymond Pontcharraud, Olivier Guillard, Bernard Fauconneau and Guylene Page
Affiliation:
Keywords: PKR, NF-&kgr;B, inflammation, APPswePS1dE9, Aβ42 load, behavioral tests
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.
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Couturier Julien, Paccalin Marc, Lafay-Chebassier Claire, Chalon Sylvie, Ingrand Isabelle, Pinguet Jeremy, Pontcharraud Raymond, Guillard Olivier, Fauconneau Bernard and Page Guylene, 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, Current Alzheimer Research 2012; 9 (3) . https://dx.doi.org/10.2174/156720512800107582
DOI https://dx.doi.org/10.2174/156720512800107582 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
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Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
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