%0 Journal Article
%A Yamanaka, Mitsugu
%A Ishikawa, Taizo
%A Griep, Angelika
%A Axt, Daisy
%A Kummer, Markus P
%A Heneka, Michael T
%T PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice.
%J The journal of neuroscience
%V 32
%N 48
%@ 0270-6474
%C Washington, DC
%I Soc.57413
%M DZNE-2020-03032
%P 17321-17331
%D 2012
%X 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.
%K Alzheimer Disease: drug therapy
%K Alzheimer Disease: metabolism
%K Alzheimer Disease: psychology
%K Amyloid beta-Protein Precursor: genetics
%K Amyloid beta-Protein Precursor: metabolism
%K Animals
%K Behavior, Animal: drug effects
%K Behavior, Animal: physiology
%K Brain: drug effects
%K Brain: metabolism
%K Cognition: drug effects
%K Cognition: physiology
%K Disease Models, Animal
%K Hypoglycemic Agents: pharmacology
%K Hypoglycemic Agents: therapeutic use
%K Maze Learning: drug effects
%K Maze Learning: physiology
%K Mice
%K Microglia: drug effects
%K Microglia: metabolism
%K PPAR gamma: agonists
%K Phagocytosis: drug effects
%K Phagocytosis: physiology
%K Pioglitazone
%K Presenilin-1: genetics
%K Presenilin-1: metabolism
%K Thiazolidinediones: pharmacology
%K Thiazolidinediones: therapeutic use
%K Amyloid beta-Protein Precursor (NLM Chemicals)
%K Hypoglycemic Agents (NLM Chemicals)
%K PPAR gamma (NLM Chemicals)
%K Presenilin-1 (NLM Chemicals)
%K Thiazolidinediones (NLM Chemicals)
%K Pioglitazone (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:23197723
%2 pmc:PMC6621845
%R 10.1523/JNEUROSCI.1569-12.2012
%U https://pub.dzne.de/record/136710