Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice.

Alexis Y Carter,Cody M Wolfe,Kyong Nyon Nam,Nicholas F Fitz,Anais Mounier,Florent Letronne,Hafsa Kamboh,Iliya Lefterov,Valerie L Reeves,Radosveta Koldamova,Stephen D Ginsberg

doi:10.1371/journal.pone.0172161

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.

Highlights

The inheritance of APOEε4 allele is the major genetic risk factor for late-onset Alzheimer disease (LOAD) [1]
We have previously demonstrated that Abca1 deficiency differentially affects AD-like phenotype in mice expressing human APOE4 or APOE3
In this study we analyzed the effect of Liver X receptors (LXRs) agonist T0 on the phenotype of Abca1 haplo-deficient APP/E3 and APP/E4 mice

Summary

Introduction

The inheritance of APOEε4 allele is the major genetic risk factor for late-onset Alzheimer disease (LOAD) [1]. AD patients, carriers of APOEε4 allele show earlier onset of the disease and higher amyloid load. The mechanism by which APOE4 affects the pathogenesis of AD remains poorly understood and it is still unclear if APOEε4 allele confers insufficient protection against beta-amyloid (Aβ) or if it has deleterious effects [5, 6]. Compared to APOEε3 carriers, the higher incidence of LOAD and an increased Aβ deposition in APOEε4 carriers might be a result of lower brain APOE protein levels, or its lower lipidation [6]. In addition to APOEε4, other low prevalence functional genetic variants are proposed as risk modifiers [7]

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