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Updated: Mar 7, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1
Alexis Y Carter1, Florent Letronne1, Nicholas F Fitz1
1Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
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.
Insights
Targeting the Liver X Receptor (LXR) pathway with agonists ameliorates Alzheimer's disease (AD) pathology in APOE4 mice. This approach enhances ABCA1 transporter function, improving APOE lipidation and cognitive deficits.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- ATP-binding cassette transporter A1 (ABCA1) is crucial for cholesterol efflux to apolipoprotein E (APOE).
- ABCA1 dysfunction and APOE isoforms, particularly APOE4, are implicated in Alzheimer's disease (AD) pathogenesis.
- Liver X Receptors (LXRs) and Retinoic X Receptors (RXRs) regulate ABCA1 expression.
Purpose of the Study:
- To investigate the therapeutic potential of an LXR agonist (T0901317) in an AD mouse model with APOE4 and ABCA1 haplo-deficiency.
- To analyze the effects of LXR activation on AD-related pathology and brain transcriptome in APP/E4/Abca1+/- mice.
Main Methods:
- Treatment of APP/E3/Abca1+/- and APP/E4/Abca1+/- mice with the LXR agonist T0901317.
- Assessment of cognitive function, Aβ oligomer levels, amyloid load, and APOE lipidation.
- Transcriptome analysis using Gene set enrichment analysis (GSEA).
Main Results:
- LXR agonist treatment ameliorated APOE4-driven pathological phenotypes and cognitive deficits in mice.
- T0901317 increased ABCA1 protein levels, enhanced APOE lipidation, and reduced Aβ oligomers.
- Transcriptome analysis revealed APOE isoform-specific responses, with significant effects on "Microtubule Based Process" and "Synapse Organization" in APP/E4/Abca1+/- mice.
Conclusions:
- Targeting the LXR-ABCA1-APOE pathway with agonists shows promise for treating AD-like pathology, especially in APOE4 carriers.
- LXR agonist treatment effectively restores cognitive function and reduces AD pathology markers in a relevant mouse model.
- The findings suggest a potential therapeutic strategy for AD patients carrying the APOEε4 allele.
