Abstract
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
Keywords: Alzheimer’s disease, astrocytes, inflammation, microglia, neuroinflammation, bromodomain, JQ1, splenomegaly.
Current Alzheimer Research
Title:The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease
Volume: 13 Issue: 9
Author(s): Marco Magistri, Dmitry Velmeshev, Madina Makhmutova, Prutha Patel, Gregory C. Sartor, Claude-Henry Volmar, Claes Wahlestedt and Mohammad Ali Faghihi
Affiliation:
Keywords: Alzheimer’s disease, astrocytes, inflammation, microglia, neuroinflammation, bromodomain, JQ1, splenomegaly.
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
Export Options
About this article
Cite this article as:
Magistri Marco, Velmeshev Dmitry, Makhmutova Madina, Patel Prutha, Sartor C. Gregory, Volmar Claude-Henry, Wahlestedt Claes and Faghihi Ali Mohammad, The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (9) . https://dx.doi.org/10.2174/1567205013666160427101832
DOI https://dx.doi.org/10.2174/1567205013666160427101832 |
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
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...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
- 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
-
Subject Index To Volume 8
Protein & Peptide Letters Update of QSAR & Docking Studies of the GSK-3 Inhibitors
Current Bioinformatics Therapeutic Strategy of Erythropoietin in Neurological Disorders
CNS & Neurological Disorders - Drug Targets Design, Synthesis and Biological Evaluation of Scutellarein Derivatives as Potential Anti-Alzheimers Disease Candidates Based on Metabolic Mechanism
Letters in Drug Design & Discovery Neural Basis of Anhedonia and Amotivation in Patients with Schizophrenia: The Role of Reward System
Current Neuropharmacology New Targets for Therapy in Polyglutamine (polyQ) Expansion Diseases
Current Drug Therapy The Indiana Alzheimer Disease Centers Symposium on Mild Cognitive Impairment. Cognitive Training in Older Adults: Lessons from the ACTIVE Study
Current Alzheimer Research Tryptamine Induces Axonopathy and Mitochondriopathy Mimicking Neurodegenerative Diseases via Tryptophanyl-tRNA Deficiency
Current Alzheimer Research Potential Roles of Selenium and Selenoproteins in the Prevention of Alzheimer's Disease
Current Topics in Medicinal Chemistry The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic Options
Current Cardiology Reviews An Effective Brain Imaging Biomarker for AD and aMCI: ALFF in Slow-5 Frequency Band
Current Alzheimer Research Blood-Brain Barrier Transport of Drugs for the Treatment of Brain Diseases
CNS & Neurological Disorders - Drug Targets Peptide-Mediated Cellular Delivery of Oligonucleotide-Based Therapeutics In Vitro: Quantitative Evaluation of Overall Efficacy Employing Easy to Handle Reporter Systems
Current Pharmaceutical Design Understanding the Obstacles to Uptake of Intervention Programmes and Services for Persons with Dementia
Current Alzheimer Research Lead Finding for Acetyl Cholinesterase Inhibitors from Natural Origin: Structure Activity Relationship and Scope
Mini-Reviews in Medicinal Chemistry Psychiatric Disorders Associated with FXTAS
Current Psychiatry Reviews The Role of Mitochondrial Dysfunction in Heart Failure and Potential Therapeutic Targets
Current Pharmaceutical Design Phosphodiesterases as Therapeutic Targets for Huntington’s Disease
Current Pharmaceutical Design A Review of Selected Adult Congenital Heart Diseases Encountered in Daily Practice
Current Cardiology Reviews The Perils, Pitfalls and Opportunities of Using High Sensitivity Cardiac Troponin
Current Medicinal Chemistry