INTERACTIONS OF APOE GENOTYPE AND RXR AGONISTS ON SOLUBLE AB AND OLIGOMERIC AB

Abstract

Apolipoprotein E (apoE) represents a promising target for modulating amyloid-β (A β) levels. Indeed, bexarotene (Bex), a retinoid X receptor (RXR) agonist, reduced soluble and insoluble levels of Aβ via increasing mouse apoE levels, although subsequent reports raise concerns regarding the mechanism of action of Bex, particularly with the human alleles of APOE. EFAD mice (overexpressing human Aβ 42 with human APOE3 or APOE4) were treated with Bex, LG268 (a more selective RXR agonist), or vehicle control in 3 treatment paradigms: T1) 7-day oral gavage (5.75-6M); T2) 7-day hydrogel (5.75-6M); and T3) 30-day hydrogel (5-6M). Hydrogel provides a steady dosage of drug throughout the awake period of the mice. Brains were harvested, dissected, and homogenized by 3-step serial extraction. In brain regions with low Aβ levels at treatment, RXR agonists did not change soluble levels of Aβ 42 and oAβ in E3FAD or E4FAD mice. In brain regions with intermediate Aβ levels, RXR agonist treatment induced an increase in soluble Aβ 42 and oAβ levels in E3FAD and E4FAD mice. However, in the hippocampus of E4FAD mice, with high Aβ levels at treatment, RXR agonists induced a decrease in soluble Aβ 42 and oAβ levels and an increase in synaptic proteins. Importantly, total apoE levels were unaffected for all treatment groups, suggesting an alternate mechanism of action for RXR agonists. Our data further demonstrate that the beneficial effects of RXR agonists in E4FAD mice are mediated via: increased ABCA1 and ABCG1 expression, increased apoE4 association with lipoproteins, increased apoE/Aβ complex levels, reduced oAβ levels and enhanced synaptic viability. Collectively, our data demonstrate that RXR agonist efficacy is determined by the levels of Aβ pathology at time of treatment, exhibiting no effect, or even an increase the levels of neurotoxic Aβ in prevention paradigms where Aβ levels are likely sub-pathological. However, in later stages of AD, RXR agonists may address the loss of function associated with APOE4 by increasing apoE4 lipidation and apoE4/Aβ complex formation. Future studies are necessary to determine whether this pathway is relevant for APOE3 carriers with high Aβ pathology, or if RXR agonists are an APOE4- specific AD therapeutic.