Retinoic Acid Isomers Facilitate Apolipoprotein E Production and Lipidation in Astrocytes through the Retinoid X Receptor/Retinoic Acid Receptor Pathway

• Published in: The Journal of biological chemistry Vol. 289; no. 16; pp. 11282 - 11292
• Main Authors: Zhao, Jing, Fu, Yuan, Liu, Chia-Chen, Shinohara, Mitsuru, Nielsen, Henrietta M., Dong, Qiang, Kanekiyo, Takahisa, Bu, Guojun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-04-2014; American Society for Biochemistry and Molecular Biology
• Subjects: Alleles; Alzheimer Disease; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Amyloid; Animals; Anticarcinogenic Agents - pharmacology; ApoE; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Astrocytes - metabolism; Astrocytes - pathology; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Bexarotene; Brain - metabolism; Brain - pathology; Cell Line, Transformed; Cholesterol; Humans; Lipoproteins - genetics; Lipoproteins - metabolism; Lipoylation; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Retinoic Acid; Retinoid; Retinoid X Receptors - genetics; Retinoid X Receptors - metabolism; Tetrahydronaphthalenes - pharmacology; Tretinoin - analogs & derivatives; Tretinoin - pharmacology; Retinoic Acid; Amyloid; ApoE; Alzheimer Disease; Cholesterol; Retinoid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.526095

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.
Background: Apolipoprotein E (apoE) isoforms influence the risk for Alzheimer disease (AD).
Results: All-trans-retinoic acid (RA), 9-cis-RA, and 13-cis-RA were identified as compounds that increase apoE expression and lipidation in astrocytes.
Conclusion: RA isomers are effective modulators of apoE production through the retinoid X receptor (RXR) and RA receptor (RAR).
Significance: RXR/RAR agonists can be explored for AD therapy.