Interactions of APOE genotype and RXR agonists on soluble Aβ and oAβ levels (LB624)

Abstract

Interactions of APOE genotype and RXR agonists on soluble Aβ and oAβ levels Kevin Koster1, Jia Luo2, Sue Lee2, Varsha Shete2, Gregory RJ Thatcher2, Mary Jo LaDu1, Leon M Tai1 There is a critical need to develop novel Alzheimer’s disease (AD) therapeutics that lower amyloid beta (Aβ) levels, as current therapeutics are failing in clinical trials. APOE4 (encodes apolipoprotein E; apoE) is the greatest AD genetic risk factor compared to APOE3. ApoE represents a promising target for modulating A levels, as it has been shown to have genotype‐specific effects on Aβ pathology in humans and mice. Recently, bexarotene (Bex), a retinoid X receptor (RXR) agonist, was shown to reduce soluble and insoluble levels of Aβ via increasing mouse apoE levels. However, subsequent data have raised concerns over the activity and mechanism of action of Bex. A major issue is that the effect of modulating human apoE on Aβ levels is unclear. Further, the levels of Aβ pathology at time of treatment may determine RXR agonist activity i.e. treatment vs prevention paradigms. Therefore, novel EFAD mice (overexpress Aβ42 and express human apoE3 or apoE4) were treated with Bex and LG268, a more selective RXR agonist. RXR agonist treatment of E3FAD and E4FAD mice with intermediate Aβ levels resulted in increased soluble Aβ42 and oligomeric Aβ levels (oAβ), with a trend to increase insoluble Aβ levels. RXR agonist treatment of E4FAD mice with high Aβ levels decreased soluble Aβ42 and oAβ levels, with no effect on insoluble Aβ. Further, our data indicate that the beneficial effects of RXR agonists are mediated through: increased ABCA1 and ABCG1 expression, increased lipidation of apoE‐containing lipoproteins, and thus increased apoE/A complex levels. Collectively these data suggest that RXR agonists may increase neurotoxic Aβ levels in prevention paradigms. However, RXR agonists may be effective for AD patients expressing APOE4 at a more advanced stage of the disease via a novel mechanism of action: enhanced apoE4 lipidation.Grant Funding Source: Supported by Alzheimer's Disease Drug Discovery Foundation