Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the RXR/RAR pathway [Cell Biology]

March 5th, 2014 by Zhao, J., Fu, Y., Liu, C.-C., Shinohara, M., Nielsen, H. M., Dong, Q., Kanekiyo, T., Bu, G.

Apolipoprotein E apoE) is the major cholesterol transport protein in the central nervous system. Among the three human APOE alleles (APOE2, APOE3, APOE4), APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) is a central event in the pathogenesis of AD. Increasing evidence demonstrates that apoE isoforms differentially regulate AD-related pathways through both Aβ-dependent and independent mechanisms; therefore, modulating apoE secretion, lipidation and function might be an attractive approach for AD therapy. We performed a drug screen for compounds that modulate apoE production in immortalized astrocytes derived from apoE3-targeted replacement mice. Here we report that retinoic acid (RA) isomers, including all-trans RA, 9-cis RA and 13-cis RA, significantly increase apoE secretion to ~4-fold of control through retinoid X receptor (RXR) and RA receptor (RAR). These effects on modulating apoE are comparable to the effects recently reported for the RXR agonist bexarotene. Furthermore, all of these compounds increased the expression of the cholesterol transporter ABCA1 and ABCG1 levels, and decreased cellular uptake of Aβ in an apoE-dependent manner. We also found that both bexarotene and 9-cis RA promote the lipidation status of apoE, of which 9-cis RA promotes a stronger effect and exhibits less cytotoxicity compared to bexarotene. Importantly, we showed that oral administration of bexarotene and 9-cis RA significantly increases apoE, ABCA1 and ABCG1 levels in mouse brains. Taken together, our results demonstrate that RXR/RAR agonists, including several RA isomers, are effective modulators of apoE secretion and lipidation, and may be explored as potential drugs for AD therapy.