136710 20240321220125.0 10.1523/JNEUROSCI.1569-12.2012 doi pmid:23197723 pmid pmc:PMC6621845 pmc 0270-6474 ISSN 1529-2401 ISSN altmetric:4243638 altmetric DZNE-2020-03032 English 610 Yamanaka, Mitsugu P:(DE-HGF)0 0 PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. Washington, DC 2012 Soc.57413 online Crossref Society for Neuroscience 2012-11-28 print Crossref Society for Neuroscience 2012-11-28 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1586874853_30145 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 344 - Clinical and Health Care Research (POF3-344) G:(DE-HGF)POF3-344 POF3-344 POF III 0 2013-05-28 Crossref https://creativecommons.org/licenses/by-nc-sa/4.0/ Dataset connected to CrossRef, PubMed, Amyloid beta-Protein Precursor NLM Chemicals Hypoglycemic Agents NLM Chemicals PPAR gamma NLM Chemicals Presenilin-1 NLM Chemicals Thiazolidinediones NLM Chemicals Pioglitazone X4OV71U42S NLM Chemicals Alzheimer Disease: drug therapy MeSH Alzheimer Disease: metabolism MeSH Alzheimer Disease: psychology MeSH Amyloid beta-Protein Precursor: genetics MeSH Amyloid beta-Protein Precursor: metabolism MeSH Animals MeSH Behavior, Animal: drug effects MeSH Behavior, Animal: physiology MeSH Brain: drug effects MeSH Brain: metabolism MeSH Cognition: drug effects MeSH Cognition: physiology MeSH Disease Models, Animal MeSH Hypoglycemic Agents: pharmacology MeSH Hypoglycemic Agents: therapeutic use MeSH Maze Learning: drug effects MeSH Maze Learning: physiology MeSH Mice MeSH Microglia: drug effects MeSH Microglia: metabolism MeSH PPAR gamma: agonists MeSH Phagocytosis: drug effects MeSH Phagocytosis: physiology MeSH Pioglitazone MeSH Presenilin-1: genetics MeSH Presenilin-1: metabolism MeSH Thiazolidinediones: pharmacology MeSH Thiazolidinediones: therapeutic use MeSH Ishikawa, Taizo P:(DE-HGF)0 1 Griep, Angelika P:(DE-HGF)0 2 Axt, Daisy P:(DE-HGF)0 3 Kummer, Markus P P:(DE-HGF)0 4 Heneka, Michael T P:(DE-2719)2000008 5 Last author 10.1523/jneurosci.1569-12.2012 Society for Neuroscience 2012-11-28 48 17321-17331 journal-article Crossref The Journal of Neuroscience 32 2012 0270-6474 10.1523/JNEUROSCI.1569-12.2012 Vol. 32, no. 48, p. 17321 - 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