title: Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice.
abstract: Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid β (Aβ), which is accompanied by a robust inflammatory response in the brain. Both of these pathogenic processes are regulated by nuclear receptors, including the liver X receptors (LXRs) and peroxisome-proliferator receptor γ (PPARγ). Agonists of LXRs have been demonstrated previously to reduce Aβ levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPARγ reduce the microglial expression of proinflammatory genes and have also been shown to modulate apoE expression. Here we investigate whether a combination therapy with both LXR and PPARγ agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPARγ agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate Aβ decreases in the hippocampus. Combined treatment with both agonists provoked a further increase in the expression of apoE and a decrease in the soluble and deposited forms of Aβ. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPARγ agonist in the combined treatment paradigm was able to counteract the elevation in plasma triglycerides that is a side effect of LXR agonist treatment. These results suggest that combined LXR/PPARγ agonist treatment merits further investigation for the treatment of AD.
authors.affiliation: From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Skerrett
authors.affiliation: the School of Medicine, University of Campinas, Campinas, Sao Paulo 13083-887, Brazil.
authors.forename: Mateus P
authors.initials: MP
authors.lastname: Pellegrino
authors.affiliation: From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Brad T
authors.initials: BT
authors.lastname: Casali
authors.affiliation: From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Laura
authors.initials: L
authors.lastname: Taraboanta
authors.affiliation: From the Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106 and gel2@case.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010316:Particle Size; D000077205:Pioglitazone; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D015415:Biomarkers; C473027:GW 3965; D018836:Inflammation Mediators; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D053764:Presenilin-1; D045162:Thiazolidinediones; D014280:Triglycerides; D000077205:Pioglitazone
keywords: Alzheimer disease; amyloid β (Aβ); apolipoprotein E (apoE); liver X receptor (LXR); microglia; peroxisome proliferator-activated receptor (PPAR)