Abstract
Agonists of the peroxisome proliferator activated receptor gamma (PPARγ) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARδ), which is expressed at higher levels in the brain than PPARγ, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARδ agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARγ agonists, PPARδ agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance.
Keywords: Amyloid, neprilysin, astrocyte, promoter, inflammation, NEP, IDE
Current Alzheimer Research
Title: A PPARdelta Agonist Reduces Amyloid Burden and Brain Inflammation in a Transgenic Mouse Model of Alzheimers Disease
Volume: 6 Issue: 5
Author(s): Sergey Kalinin, Jill C. Richardson and Douglas L. Feinstein
Affiliation:
Keywords: Amyloid, neprilysin, astrocyte, promoter, inflammation, NEP, IDE
Abstract: Agonists of the peroxisome proliferator activated receptor gamma (PPARγ) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARδ), which is expressed at higher levels in the brain than PPARγ, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARδ agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARγ agonists, PPARδ agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance.
Export Options
About this article
Cite this article as:
Kalinin Sergey, Richardson C. Jill and Feinstein L. Douglas, A PPARdelta Agonist Reduces Amyloid Burden and Brain Inflammation in a Transgenic Mouse Model of Alzheimers Disease, Current Alzheimer Research 2009; 6 (5) . https://dx.doi.org/10.2174/156720509789207949
DOI https://dx.doi.org/10.2174/156720509789207949 |
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
-
Animal Models of Central Nervous System Immune-Mediated Diseases: Therapeutic Interventions with Bioactive Peptides and Mimetics
Current Medicinal Chemistry The Therapeutic use of the Zonulin Inhibitor AT-1001 (Larazotide) for a Variety of Acute and Chronic Inflammatory Diseases
Current Medicinal Chemistry Interferon-γ-Induced Neurotoxicity of Human Astrocytes
CNS & Neurological Disorders - Drug Targets Anti-inflammatory Action of Green Tea
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Heparan Sulphate as a Regulator of Leukocyte Recruitment in Inflammation
Current Protein & Peptide Science Activation of the dsRNA-Activated Protein Kinase PKR in Mitochondrial Dysfunction and Inflammatory Stress in Metabolic Syndrome
Current Pharmaceutical Design Therapeutic Strategies in Parkinsons Disease
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Temporal Progression of Kainic Acid Induced Changes in Vascular Laminin Expression in Rat Brain with Neuronal and Glial Correlates
Current Neurovascular Research TCR Peptide Vaccination in Multiple Sclerosis: Boosting a Deficient Natural Regulatory Network that may Involve TCR-Specific CD4+CD25+ Treg Cells
Current Drug Targets - Inflammation & Allergy Functional Interactions Between B Lymphocytes and the Innate Immune System
Infectious Disorders - Drug Targets Endocannabinoids and their Involvement in the Neurovascular System
Current Neurovascular Research Molecular Docking Study of a Series of Substituted Xanthone Derivatives as Novel COX-2 Inhibitors Targeting Prostaglandin Endoperoxide Synthase -2
Current Enzyme Inhibition Editorial [Hot Topic: Stem Cell Based Therapy for Autoimmunity (Guest Editor: Frank Alderuccio)]
Current Stem Cell Research & Therapy Inhibitory Smad7: Emerging Roles in Health and Disease
Current Molecular Pharmacology Interleukin 10 in Antiviral Responses
Current Immunology Reviews (Discontinued) Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition
Current Medicinal Chemistry The Main Receptors Involved in the COVID-19: A Systematic Review and Meta-Analysis
Current Medicinal Chemistry Editorial: Steroid-Dependent Management of Biological Responses in the Nervous System
CNS & Neurological Disorders - Drug Targets Micro- and Nano-particulate Strategies for Antigen Specific Immune Tolerance to Treat Autoimmune Diseases
Pharmaceutical Nanotechnology Strategies to Convert PACAP from a Hypophysiotropic Neurohormone Into a Neuroprotective Drug
Current Pharmaceutical Design