Combined Liver X Receptor/peroxisome Proliferator-activated Receptor Agonist Treatment Reduces Amyloid Levels And Improves Behavior In Amyloid Precursor Protein/presenilin 1 Mice

dc.creatorSkerrett
dc.creatorRebecca; Pellegrino
dc.creatorMateus P.; Casali
dc.creatorBrad T.; Taraboanta
dc.creatorLaura; Landreth
dc.creatorGary E.
dc.date2015-AUG
dc.date2016-06-07T13:34:59Z
dc.date2016-06-07T13:34:59Z
dc.date.accessioned2018-03-29T01:50:33Z
dc.date.available2018-03-29T01:50:33Z
dc.identifier
dc.identifierCombined Liver X Receptor/peroxisome Proliferator-activated Receptor Agonist Treatment Reduces Amyloid Levels And Improves Behavior In Amyloid Precursor Protein/presenilin 1 Mice. Amer Soc Biochemistry Molecular Biology Inc, v. 290, p. 21591-21602 AUG-2015.
dc.identifier0021-9258
dc.identifierWOS:000360637600032
dc.identifier10.1074/jbc.M115.652008
dc.identifierhttp://www.jbc.org/content/290/35/21591
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/244024
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1307722
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionBackground: In the brain, the type II nuclear receptors LXR and PPAR control cholesterol efflux and inflammation, key processes in Alzheimer disease pathology. Results: Combining the LXR and PPAR agonists decreases the levels of A and inflammation, resulting in improved cognition. Conclusion: The LXR and PPAR agonists complement each other, possibly by modulating microglial function. Significance: Targeting multiple nuclear receptors expands the therapeutic opportunities for AD treatment. Alzheimer disease (AD) is characterized by the extracellular accumulation of amyloid (A), 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 (PPAR). Agonists of LXRs have been demonstrated previously to reduce A levels and improve cognitive deficits in AD mouse models by inducing the transcription and lipidation of apolipoprotein E (apoE). Agonists targeting PPAR 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 PPAR agonists results in increased benefits in an AD mouse model. We found that the LXR agonist GW3965 and the PPAR agonist pioglitazone were individually able to increase the levels of apoE and related genes, decrease the expression of proinflammatory genes, and facilitate A 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 A. The decrease in plaques was associated with increased colocalization between microglia and plaques. In addition, the PPAR 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/PPAR agonist treatment merits further investigation for the treatment of AD.
dc.description290
dc.description35
dc.description
dc.description21591
dc.description21602
dc.descriptionNational Institutes of Health [R01 AG030482, 5T32NS067431-13]
dc.descriptionGail and Elliott Schlang Philanthropic Fund
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionCAPES [5758/12-2]
dc.description
dc.description
dc.description
dc.languageen
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.publisher
dc.publisherBETHESDA
dc.relationJOURNAL OF BIOLOGICAL CHEMISTRY
dc.rightsembargo
dc.sourceWOS
dc.subjectAlzheimers-disease
dc.subjectPpar-gamma
dc.subjectA-beta
dc.subjectTransgenic Mice
dc.subjectNuclear Receptors
dc.subjectApolipoprotein-e
dc.subjectMouse Model
dc.subjectMemory Deficits
dc.subjectLxr Agonist
dc.subjectCognitive Deficits
dc.titleCombined Liver X Receptor/peroxisome Proliferator-activated Receptor Agonist Treatment Reduces Amyloid Levels And Improves Behavior In Amyloid Precursor Protein/presenilin 1 Mice
dc.typeArtículos de revistas


Este ítem pertenece a la siguiente institución