title: PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
abstract: 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.
authors.affiliation: Clinical Neuroscience Unit, Department of Neurology, University of Bonn Medical Center, 53127 Bonn, Germany.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Yamanaka
authors.forename: Taizo
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Angelika
authors.initials: A
authors.lastname: Griep
authors.forename: Daisy
authors.initials: D
authors.lastname: Axt
authors.forename: Markus P
authors.initials: MP
authors.lastname: Kummer
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D000077205:Pioglitazone; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016564:Amyloid beta-Protein Precursor; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D053764:Presenilin-1; D045162:Thiazolidinediones; D000077205:Pioglitazone