title: Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice.
abstract: ATP-binding cassette transporter A1 (ABCA1) controls cholesterol and phospholipid efflux to lipid-poor apolipoprotein E (APOE) and is transcriptionally controlled by Liver X receptors (LXRs) and Retinoic X Receptors (RXRs). In APP transgenic mice, lack of Abca1 increased Aβ deposition and cognitive deficits. Abca1 haplo-deficiency in mice expressing human APOE isoforms, increased level of Aβ oligomers and worsened memory deficits, preferentially in APOE4 mice. In contrast upregulation of Abca1 by LXR/RXR agonists significantly ameliorated pathological phenotype of those mice. The goal of this study was to examine the effect of LXR agonist T0901317 (T0) on the phenotype and brain transcriptome of APP/E3 and APP/E4 Abca1 haplo-deficient (APP/E3/Abca1+/- and APP/E4/Abca1+/-) mice. Our data demonstrate that activated LXRs/RXR ameliorated APOE4-driven pathological phenotype and significantly affected brain transcriptome. We show that in mice expressing either APOE isoform, T0 treatment increased mRNA level of genes known to affect brain APOE lipidation such as Abca1 and Abcg1. In both APP/E3/Abca1+/- and APP/E4/Abca1+/- mice, the application of LXR agonist significantly increased ABCA1 protein level accompanied by an increased APOE lipidation, and was associated with restoration of APOE4 cognitive deficits, reduced levels of Aβ oligomers, but unchanged amyloid load. Finally, using Gene set enrichment analysis we show a significant APOE isoform specific response to LXR agonist treatment: Gene Ontology categories "Microtubule Based Process" and "Synapse Organization" were differentially affected in T0-treated APP/E4/Abca1+/- mice. Altogether, the results are suggesting that treatment of APP/E4/Abca1+/- mice with LXR agonist T0 ameliorates APOE4-induced AD-like pathology and therefore targeting the LXR-ABCA1-APOE regulatory axis could be effective as a potential therapeutic approach in AD patients, carriers of APOEε4.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Alexis Y
authors.initials: AY
authors.lastname: Carter
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Florent
authors.initials: F
authors.lastname: Letronne
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Fitz
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Anais
authors.initials: A
authors.lastname: Mounier
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Cody M
authors.initials: CM
authors.lastname: Wolfe
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Kyong Nyon
authors.initials: KN
authors.lastname: Nam
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Reeves
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hafsa
authors.initials: H
authors.lastname: Kamboh
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Iliya
authors.identifier: http://orcid.org/0000-0002-0249-0280
authors.initials: I
authors.lastname: Lefterov
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Radosveta
authors.initials: R
authors.lastname: Koldamova
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D016000:Cluster Analysis; D005239:Fear; D005260:Female; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D000071518:Liver X Receptors / Q000819:agonists*; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D010641:Phenotype; D012984:Software; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D000071518:Liver X Receptors; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse