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.
Export Options
About this article
Cite this article as:
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
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
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
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
GSK3 Inhibitors and Disease
Mini-Reviews in Medicinal Chemistry Regulation of Neurotrophic Factors and Energy Metabolism by Antidepressants in Astrocytes
Current Drug Targets Transcription Factors in Autoimmune Diseases
Current Pharmaceutical Design Peroxisome Proliferator-Activated Receptor (PPAR) Agonists as Promising New Medications for Drug Addiction: Preclinical Evidence
Current Drug Targets Chemical and Structural Features Influencing the Biological Activity of Curcumin
Current Pharmaceutical Design Editorial[Hot Topic: Tau Protein and Alzheimers Disease. New Paradigms and Future Challenges (Guest Editor: Ricardo B. Maccioni)]
Current Alzheimer Research The Dual Role of Interleukin-25 in the Control of Immune-Mediated Pathologies
Current Molecular Medicine Cell-based Assays for Assessing Toxicity: A Basic Guide
Medicinal Chemistry Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants
Current Neuropharmacology Development of New H1 Antihistamines: The Importance of Pharmacokinetics in the Evaluation of Safe and Therapeutically Effective Agents
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Synthesis and Biological Evaluation of Curcumin-Nitroxide-Based Molecular Hybrids as Antioxidant and Anti-Proliferative Agents
Medicinal Chemistry Drastic Effects on Fibril Formation of Amyloid-β Peptides by the Addition of Amino Acid Residue Units to the Termini
Protein & Peptide Letters Reconstruction of the Network of Experimentally Validated AMP-Drug Combinations Against Pseudomonas aeruginosa Infections
Current Bioinformatics Editorial [Hot Topic:Melanin-Concentrating Hormone (MCH) (Guest Editor: Andrew J. Souers)]
Current Topics in Medicinal Chemistry Cytochrome P450 and the Biological Clock in Mammals
Current Drug Metabolism Fine Tuning of Intracellular Ca<sup>2+</sup> Content by Pharmacological Agents – A Strategy to Prevent Synapse Loss in Alzheimer Disease Hippocampal Neurons
Current Alzheimer Research Design, Synthesis, <i>In Silico</i> and <i>In Vitro</i> Studies of Substituted 1, 2, 3, 4- Tetrahydro Pyrimidine Phosphorus Derivatives
Combinatorial Chemistry & High Throughput Screening Structure- and Ligand-Based Approaches to Evaluate Aporphynic Alkaloids from Annonaceae as Multi-Target Agent Against Leishmania donovani
Current Pharmaceutical Design Off-Label Use of Sunitinib in Patients with Advanced, Epithelial Thyroid Cancer: A Retrospective Analysis
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Central Nervous System Activities of Indole Derivatives: An Overview
Central Nervous System Agents in Medicinal Chemistry