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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...

Soluble oligomeric Aβ (oAβ) is a neurotoxic aggregate thought to be a proximal cause of Alzheimer disease (AD). Chronic inflammation of glial cells induced by oAβ-induced likely results in both direct neurotoxicity and decreased phagocytic clearance of Aβ and cellular debris. The strongest genetic risk factor for AD is the e4 allele of the APOE gene. As APOE4 is associated with a proinflammatory response compared to APOE3, we determined the APOE-specific neuroinflammatory phenotype in novel EFAD transgenic mice, which overexpress human Aβ42 and apolipoprotein E (apoE). Overall, our data are consistent with an increased pro-inflammatory, anti-phagocytic (M1) and reduced anti-inflammatory, repair, (M2) response in E4FAD compared to E3FAD mice. To determine the mechanism underlying these effects and test our hypothesis that TLR4 signaling mediates Aβ-induced APOE-modulated neuroinflammation, a primary glial screen was developed. LPS- and oAβ-induced secretion of TNF-α is concentration dependent and higher wi...