Apolipoprotein E (
apoE) is the major
cholesterol transport protein in the brain. Among the three human
APOE alleles (
APOE2,
APOE3, and
APOE4),
APOE4 is the strongest genetic risk factor for
late-onset Alzheimer disease (AD). The accumulation of
amyloid-β (Aβ) is a central event in AD pathogenesis. 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. These effects on modulating
apoE are comparable with 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. Both
bexarotene and 9-cis-RA promote the lipidation status of
apoE, in which 9-cis-RA promotes a stronger effect and exhibits less cytotoxicity compared with
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/RA receptor agonists, including several RA isomers, are effective modulators of
apoE secretion and lipidation and may be explored as potential drugs for AD
therapy.