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@ARTICLE{Yamanaka:136710,
      author       = {Yamanaka, Mitsugu and Ishikawa, Taizo and Griep, Angelika
                      and Axt, Daisy and Kummer, Markus P and Heneka, Michael T},
      title        = {{PPAR}γ/{RXR}α-induced and {CD}36-mediated microglial
                      amyloid-β phagocytosis results in cognitive improvement in
                      amyloid precursor protein/presenilin 1 mice.},
      journal      = {The journal of neuroscience},
      volume       = {32},
      number       = {48},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.57413},
      reportid     = {DZNE-2020-03032},
      pages        = {17321-17331},
      year         = {2012},
      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.},
      keywords     = {Alzheimer Disease: drug therapy / Alzheimer Disease:
                      metabolism / Alzheimer Disease: psychology / Amyloid
                      beta-Protein Precursor: genetics / Amyloid beta-Protein
                      Precursor: metabolism / Animals / Behavior, Animal: drug
                      effects / Behavior, Animal: physiology / Brain: drug effects
                      / Brain: metabolism / Cognition: drug effects / Cognition:
                      physiology / Disease Models, Animal / Hypoglycemic Agents:
                      pharmacology / Hypoglycemic Agents: therapeutic use / Maze
                      Learning: drug effects / Maze Learning: physiology / Mice /
                      Microglia: drug effects / Microglia: metabolism / PPAR
                      gamma: agonists / Phagocytosis: drug effects / Phagocytosis:
                      physiology / Pioglitazone / Presenilin-1: genetics /
                      Presenilin-1: metabolism / Thiazolidinediones: pharmacology
                      / Thiazolidinediones: therapeutic use / Amyloid beta-Protein
                      Precursor (NLM Chemicals) / Hypoglycemic Agents (NLM
                      Chemicals) / PPAR gamma (NLM Chemicals) / Presenilin-1 (NLM
                      Chemicals) / Thiazolidinediones (NLM Chemicals) /
                      Pioglitazone (NLM Chemicals)},
      cin          = {Pre 2020 / AG Heneka2},
      ddc          = {610},
      cid          = {I:(DE-2719)999999 / I:(DE-2719)1011303},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:23197723},
      pmc          = {pmc:PMC6621845},
      doi          = {10.1523/JNEUROSCI.1569-12.2012},
      url          = {https://pub.dzne.de/record/136710},
}