PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice
| Autor: | Angelika Griep, Mitsugu Yamanaka, Daisy Axt, Markus P. Kummer, Michael T. Heneka, Taizo Ishikawa |
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| Rok vydání: | 2012 |
| Předmět: |
psychology [Alzheimer Disease]
Journal Club CD36 metabolism [Microglia] drug effects [Microglia] Amyloid beta-Protein Precursor Mice Cognition metabolism [Amyloid beta-Protein Precursor] drug effects [Behavior Animal] Amyloid precursor protein drug therapy [Alzheimer Disease] Retinoid Receptor Behavior Animal biology metabolism [Presenilin-1] General Neuroscience physiology [Cognition] Brain genetics [Presenilin-1] Cell biology physiology [Behavior Animal] Biochemistry genetics [Amyloid beta-Protein Precursor] drug effects [Cognition] drug effects [Brain] physiology [Phagocytosis] Microglia metabolism [Alzheimer Disease] medicine.drug_class Phagocytosis pharmacology [Hypoglycemic Agents] pharmacology [Thiazolidinediones] drug effects [Phagocytosis] drug effects [Maze Learning] Presenilin physiology [Maze Learning] Downregulation and upregulation Alzheimer Disease Presenilin-1 medicine Animals Hypoglycemic Agents ddc:610 Scavenger receptor Maze Learning therapeutic use [Thiazolidinediones] Pioglitazone PPAR gamma Disease Models Animal metabolism [Brain] biology.protein therapeutic use [Hypoglycemic Agents] Thiazolidinediones agonists [PPAR gamma] |
| Zdroj: | The journal of neuroscience 32(48), 17321-17331 (2012). doi:10.1523/JNEUROSCI.1569-12.2012 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1569-12.2012 |
| Popis: | Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosisin vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD. |
| Databáze: | OpenAIRE |
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