title: Activation of the nuclear receptor PPARδ is neuroprotective in a transgenic mouse model of Alzheimer's disease through inhibition of inflammation.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a multifactorial disorder associated with the accumulation of soluble forms of beta-amyloid (Aβ) and its subsequent deposition into plaques. One of the major contributors to neuronal death is chronic and uncontrolled inflammatory activation of microglial cells around the plaques and their secretion of neurotoxic molecules. A shift in microglial activation towards a phagocytic phenotype has been proposed to confer benefit in models of AD. Peroxisome proliferator activator receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory activation properties and PPARδ agonism leads to reduction in brain Aβ levels in 5XFAD mice. This study was carried out to elucidate the involvement of microglial activation in the PPARδ-mediated reduction of Aβ burden and subsequent outcome to neuronal survival in a 5XFAD mouse model of AD.
  
  
  METHODS
  5XFAD mice were orally treated with the PPARδ agonist GW0742 for 2 weeks. The brain Aβ load, glial activation, and neuronal survival were assessed by immunohistochemistry and quantitative PCR. In addition, the ability of GW0742 to prevent direct neuronal death as well as inflammation-induced neuron death was analyzed in vitro.
  
  
  RESULTS
  Our results show for the first time that a short treatment period of 5XFAD mice was effective in reducing the parenchymal Aβ load without affecting the levels of intraneuronal Aβ. This was concomitant with a decrease in overall microglial activation and reduction in proinflammatory mediators. Instead, microglial immunoreactivity around Aβ deposits was increased. Importantly, the reduction in the proinflammatory milieu elicited by GW0742 treatment resulted in attenuation of neuronal loss in vivo in the subiculum of 5XFAD mice. In addition, whereas GW0742 failed to protect primary neurons against glutamate-induced cell death, it prevented inflammation-induced neuronal death in microglia-neuron co-cultures in vitro.
  
  
  CONCLUSIONS
  This study demonstrates that GW0742 treatment has a prominent anti-inflammatory effect in 5XFAD mice and suggests that PPARδ agonists may have therapeutic utility in treating AD.
authors.affiliation: Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. tarja.malm@uef.fi.|Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. tarja.malm@uef.fi.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.affiliation: Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. mxh534@case.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Mariani
authors.affiliation: Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. lxd156@case.edu.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Donovan
authors.affiliation: Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. len11@case.edu.
authors.forename: Lee
authors.initials: L
authors.lastname: Neilson
authors.affiliation: Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. gel2@case.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000893:Anti-Inflammatory Agents; D002135:Calcium-Binding Proteins; D015815:Cell Adhesion Molecules; D015922:Complement C1q; D003176:Complement C3; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D047494:PPAR delta; D010751:Phosphopyruvate Hydratase; D013844:Thiazoles; C491049:Aif1 protein, mouse; C120427:LEEP-CAM protein, human; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds