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000136710 041__ $$aEnglish
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000136710 1001_ $$0P:(DE-HGF)0$$aYamanaka, Mitsugu$$b0
000136710 245__ $$aPPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
000136710 260__ $$aWashington, DC$$bSoc.57413$$c2012
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000136710 520__ $$aAlzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.
000136710 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x0
000136710 542__ $$2Crossref$$i2013-05-28$$uhttps://creativecommons.org/licenses/by-nc-sa/4.0/
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000136710 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000136710 650_7 $$2NLM Chemicals$$aHypoglycemic Agents
000136710 650_7 $$2NLM Chemicals$$aPPAR gamma
000136710 650_7 $$2NLM Chemicals$$aPresenilin-1
000136710 650_7 $$2NLM Chemicals$$aThiazolidinediones
000136710 650_7 $$0X4OV71U42S$$2NLM Chemicals$$aPioglitazone
000136710 650_2 $$2MeSH$$aAlzheimer Disease: drug therapy
000136710 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000136710 650_2 $$2MeSH$$aAlzheimer Disease: psychology
000136710 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: genetics
000136710 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000136710 650_2 $$2MeSH$$aAnimals
000136710 650_2 $$2MeSH$$aBehavior, Animal: drug effects
000136710 650_2 $$2MeSH$$aBehavior, Animal: physiology
000136710 650_2 $$2MeSH$$aBrain: drug effects
000136710 650_2 $$2MeSH$$aBrain: metabolism
000136710 650_2 $$2MeSH$$aCognition: drug effects
000136710 650_2 $$2MeSH$$aCognition: physiology
000136710 650_2 $$2MeSH$$aDisease Models, Animal
000136710 650_2 $$2MeSH$$aHypoglycemic Agents: pharmacology
000136710 650_2 $$2MeSH$$aHypoglycemic Agents: therapeutic use
000136710 650_2 $$2MeSH$$aMaze Learning: drug effects
000136710 650_2 $$2MeSH$$aMaze Learning: physiology
000136710 650_2 $$2MeSH$$aMice
000136710 650_2 $$2MeSH$$aMicroglia: drug effects
000136710 650_2 $$2MeSH$$aMicroglia: metabolism
000136710 650_2 $$2MeSH$$aPPAR gamma: agonists
000136710 650_2 $$2MeSH$$aPhagocytosis: drug effects
000136710 650_2 $$2MeSH$$aPhagocytosis: physiology
000136710 650_2 $$2MeSH$$aPioglitazone
000136710 650_2 $$2MeSH$$aPresenilin-1: genetics
000136710 650_2 $$2MeSH$$aPresenilin-1: metabolism
000136710 650_2 $$2MeSH$$aThiazolidinediones: pharmacology
000136710 650_2 $$2MeSH$$aThiazolidinediones: therapeutic use
000136710 7001_ $$0P:(DE-HGF)0$$aIshikawa, Taizo$$b1
000136710 7001_ $$0P:(DE-HGF)0$$aGriep, Angelika$$b2
000136710 7001_ $$0P:(DE-HGF)0$$aAxt, Daisy$$b3
000136710 7001_ $$0P:(DE-HGF)0$$aKummer, Markus P$$b4
000136710 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael T$$b5$$eLast author
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