ArticleThe Journal of biological chemistry2014
Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 72 citations in OpenAlex.
- Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease.Alzheimer's research & therapy · 2016Trial
- HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Brain Single-Cell Transcriptional Responses to Bexarotene-Activated RXR in an Alzheimer's Disease Model.International journal of molecular sciences · 2026Article
- Vivaria housing conditions expose sex differences in brain oxidation, microglial activation, and immune system states in aged hAPOE4 mice.Experimental brain research · 2024Article
- Low Density Lipoprotein Receptor-related Protein 2 Expression and Function in Cultured Astrocytes and Microglia.Neurochemical research · 2024Article
- Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches.Frontiers in aging neuroscience · 2024Review
- Article
- Behavioral and cognitive performance of humanized APOEε3/ε3 liver mice in relation to plasma apolipoprotein E levels.Scientific reports · 2023Article
- Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.Nature neuroscience · 2022Article
- Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice.Molecular psychiatry · 2022Article
- Lipoproteins in the Central Nervous System: From Biology to Pathobiology.Annual review of biochemistry · 2022Review
- APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.Acta neuropathologica · 2022Article
- ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.Neuron · 2022Review
- Modulation of retinoid-X-receptors differentially regulates expression of apolipoprotein genes apoc1 and apoeb by zebrafish microglia.Biology open · 2022Article
- The Development of Pharmacological Therapies for Alzheimer's Disease.Neurology and therapy · 2021Review
- APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.Molecular neurodegeneration · 2021Article
- Dichlorodiphenyltrichloroethane Impairs Amyloid Beta Clearance by Decreasing Liver X Receptor α Expression.Frontiers in aging neuroscience · 2021Article
- Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer's Disease.Frontiers in pharmacology · 2021Article
- Alzheimer's Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α.Cells · 2020Review
- Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.