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.

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease

“…In the past 10 years, we and others using a number of different in vivo models and behavioural paradigms have validated the initial findings that LXR agonists are able to reverse the cognitive impairments in AD model mice (Carter et al, ; Donkin et al, ; Fitz et al, ; Fitz et al, ; Vanmierlo et al, ; Wesson et al, ). The ability of LXR agonists to reverse cognitive deficits in a mouse AD model appears to be reliant on intact ABCA1 (Carter et al, ; Donkin et al, ; Fitz et al, ; Sandoval‐Hernandez et al, ). Donkin et al () presented that an 8‐week treatment of a high GW3965 dose during the early stages of amyloid deposition could diminish the levels of senile plaques in an APP/PS1 mouse model, which was dependent on functioning Abca1.…”

“…This has resulted in a number of articles exploring the potential of LXR agonists to improve cognitive performance, increase the clearance of Aβ, and diminish senile plaque levels. In the past 10 years, we and others using a number of different in vivo models and behavioural paradigms have validated the initial findings that LXR agonists are able to reverse the cognitive impairments in AD model mice (Carter et al, 2017;Donkin et al, 2010;Fitz et al, 2010;Fitz et al, 2014;Vanmierlo et al, 2011;Wesson et al, 2011).…”

“…In APP23 mice, 7 weeks of T0901317 significantly reduced the Thioflavin S‐positive plaque area in the brain (Terwel et al, ). Cognitive performance was restored; however, the levels of plaques were unchanged following T0901317 treatment in APP/PS1 mice that express human APOE3 or APOE4 and are haplodeficient in Abca1 (Carter et al, ). Again suggesting the importance of Abca1 in the mechanism of action of LXR agonists.…”

“…We identified an enrichment of genes associated with GO categories “Microtubule Based Process” and “Synapse Organization and Biosynthesis” in the brain of APP/PS1 mice expressing APOE4 and Abca1 haplodeficient treated with T0901317. Members of the β‐protocadherin family, which are essential in establishing functional synapses, were also up‐regulated in these APOE4 mice (Carter et al, ). These studies illustrate the ability of LXR agonism to impact synaptic function and integrity and furthermore alleviate the accelerated synaptopathy observed in AD and characteristic of APOE4 expression.…”

“…The ability of LXR agonists to reverse cognitive deficits in a mouse AD model appears to be reliant on intact ABCA1 (Carter et al, 2017;Donkin et al, 2010;Fitz et al, 2010;. Donkin et al (2010) presented that an 8-week treatment of a high GW3965 dose during the early stages of amyloid deposition could diminish the levels of senile plaques in an APP/PS1 mouse model, which was dependent on functioning Abca1.…”