engYamanaka, MitsuguIshikawa, TaizoGriep, AngelikaAxt, DaisyKummer, Markus PHeneka, Michael TPPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.info:eu-repo/classification/ddc/610Alzheimer Disease: drug therapyAlzheimer Disease: metabolismAlzheimer Disease: psychologyAmyloid beta-Protein Precursor: geneticsAmyloid beta-Protein Precursor: metabolismAnimalsBehavior, Animal: drug effectsBehavior, Animal: physiologyBrain: drug effectsBrain: metabolismCognition: drug effectsCognition: physiologyDisease Models, AnimalHypoglycemic Agents: pharmacologyHypoglycemic Agents: therapeutic useMaze Learning: drug effectsMaze Learning: physiologyMiceMicroglia: drug effectsMicroglia: metabolismPPAR gamma: agonistsPhagocytosis: drug effectsPhagocytosis: physiologyPioglitazonePresenilin-1: geneticsPresenilin-1: metabolismThiazolidinediones: pharmacologyThiazolidinediones: therapeutic useAmyloid beta-Protein PrecursorHypoglycemic AgentsPPAR gammaPresenilin-1ThiazolidinedionesPioglitazoneAlzheimer'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.The journal of neuroscience 32(48), 17321-17331 (2012). doi:10.1523/JNEUROSCI.1569-12.2012info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionSoc.574132012info:eu-repo/semantics/closedAccessDEhttps://pub.dzne.de/record/136710https://pub.dzne.de/search?p=id:%22DZNE-2020-03032%22Researchersinfo:eu-repo/semantics/altIdentifier/issn/1529-2401info:eu-repo/semantics/altIdentifier/issn/0270-6474info:eu-repo/semantics/altIdentifier/pmid/pmid:23197723info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.1569-12.2012