17 Yamanaka, Mitsugu Ishikawa, Taizo Griep, Angelika Axt, Daisy Kummer, Markus P Heneka, Michael T Pre 2020 AG Heneka2 The journal of neuroscience The journal of neuroscience Soc.57413 Washington, DC 0270-6474 10.1523/JNEUROSCI.1569-12.2012 English 17321-17331 48 32 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 phagocytosis in 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. PUB:(DE-HGF)16, ; 0, ; Alzheimer Disease: drug therapy Alzheimer Disease: metabolism Alzheimer Disease: psychology Amyloid beta-Protein Precursor: genetics Amyloid beta-Protein Precursor: metabolism Animals Behavior, Animal: drug effects Behavior, Animal: physiology Brain: drug effects Brain: metabolism Cognition: drug effects Cognition: physiology Disease Models, Animal Hypoglycemic Agents: pharmacology Hypoglycemic Agents: therapeutic use Maze Learning: drug effects Maze Learning: physiology Mice Microglia: drug effects Microglia: metabolism PPAR gamma: agonists Phagocytosis: drug effects Phagocytosis: physiology Pioglitazone Presenilin-1: genetics Presenilin-1: metabolism Thiazolidinediones: pharmacology Thiazolidinediones: therapeutic use Amyloid beta-Protein Precursor Hypoglycemic Agents PPAR gamma Presenilin-1 Thiazolidinediones Pioglitazone Journal Article 2012 DZNE-2020-03032 2012 pmc:PMC6621845 pmid:23197723 https://pub.dzne.de/record/136710 https://doi.org/10.1523/JNEUROSCI.1569-12.2012