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
-
High Dose Immunoglobulin (IVIG) May Reduce the Incidence of Langerhans Cell Histiocytosis (LCH)-Associated Central Nervous System Involvement
CNS & Neurological Disorders - Drug Targets A Systematic Review on the Sinomenine Derivatives
Mini-Reviews in Medicinal Chemistry Adult Stem Cells for Cartilage Tissue Engineering and Regeneration
Current Rheumatology Reviews Dipeptidyl Peptidase-4 Inhibition: Linking Chemical Properties to Clinical Safety
Current Medicinal Chemistry Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala
Current Neuropharmacology Design, Synthesis, and Anti-Neuroinflammatory Activity of Amide- Containing Dithiolethiones
Medicinal Chemistry Instructions from the Vascular System - Directing Neural Stem Cell Fate in Health and Disease
Current Medicinal Chemistry Vitamin D: A Pleiotropic Hormone with Possible Psychotropic Activities
Current Medicinal Chemistry Meet Our Editorial Board Member
CNS & Neurological Disorders - Drug Targets S100A9 as a Pharmacological Target Molecule in Inflammation and Cancer
Endocrine, Metabolic & Immune Disorders - Drug Targets The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders
Current Pharmaceutical Design The Endocrine Regulation of Stem Cells: Physiological Importance and Pharmacological Potentials for Cell-Based Therapy
Current Stem Cell Research & Therapy The Renin-Angiotensin System and the Neurodegenerative Diseases: A Brief Review
Protein & Peptide Letters Indoleamine 2,3-Dioxygenase in Materno-Fetal Interaction
Current Drug Metabolism Neuroproteomics and the Detection of Regulatory Phosphosites
Current Proteomics A Central Role for ATP Signalling in Glial Interactions in the CNS
Current Drug Targets Targeting Kinin Receptors for the Treatment of Neurological Diseases
Current Pharmaceutical Design Matrix Metalloproteinase Dependent Cleavage of Cell Adhesion Molecules in the Pathogenesis of CNS Dysfunction with HIV and Methamphetamine
Current HIV Research Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health
Inflammation & Allergy - Drug Targets (Discontinued) Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors as Therapeutics: Rationales, Controversies, Clinical Experience
Current Drug Targets