Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway.

Abstract

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.

• Authors: Jing Zhao, Yuan Fu, Chia-Chen Liu, Mitsuru Shinohara, Henrietta M Nielsen, Qiang Dong, Takahisa Kanekiyo, Guojun Bu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 16 Pg. 11282-11292 (Apr 18 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24599963 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA1 protein, human
• ABCA1 protein, mouse
• ABCG1 protein, human
• ABCG1 protein, mouse
• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters
• Anticarcinogenic Agents
• Apolipoproteins E
• Lipoproteins
• Nerve Tissue Proteins
• Receptors, Retinoic Acid
• Retinoid X Receptors
• Tetrahydronaphthalenes
• 9,13-retinoic acid
• Tretinoin
• Bexarotene

Topics

• ATP Binding Cassette Transporter 1 (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Alleles
• Alzheimer Disease (drug therapy, genetics, metabolism)
• Animals
• Anticarcinogenic Agents (pharmacology)
• Apolipoproteins E (genetics, metabolism)
• Astrocytes (metabolism, pathology)
• Bexarotene
• Brain (metabolism, pathology)
• Cell Line, Transformed
• Humans
• Lipoproteins (genetics, metabolism)
• Lipoylation
• Mice
• Mice, Transgenic
• Nerve Tissue Proteins (genetics, metabolism)
• Receptors, Retinoic Acid (genetics, metabolism)
• Retinoid X Receptors (genetics, metabolism)
• Tetrahydronaphthalenes (pharmacology)
• Tretinoin (analogs & derivatives, pharmacology)