title: 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.affiliation: From the Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200032, China,; the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and; the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Henrietta M
authors.initials: HM
authors.lastname: Nielsen
authors.affiliation: From the Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: the Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and; the Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China. Electronic address: bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D000077610:Bexarotene; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D054878:Lipoylation; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016588:Anticarcinogenic Agents; D001057:Apolipoproteins E; D000077610:Bexarotene; D008074:Lipoproteins; D009419:Nerve Tissue Proteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014212:Tretinoin; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; C105492:9,13-retinoic acid
keywords: Alzheimer Disease; Amyloid; ApoE; Cholesterol; Retinoic Acid; Retinoid