ArticleThe Journal of biological chemistry2014
Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo.
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 62 papers.
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Who cites it
62 citing papers in PubMed, 97 citations in OpenAlex.
- Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease.Alzheimer's research & therapy · 2016Trial
- Brain Single-Cell Transcriptional Responses to Bexarotene-Activated RXR in an Alzheimer's Disease Model.International journal of molecular sciences · 2026Article
- Mechanisms, Mediators, and Pharmacological Approaches Targeting Brain Cholesterol Transport in Alzheimer's Disease.Current pharmaceutical design · 2026Review
- Oligodendrocyte dysfunction in neurodegenerative diseases: pathological features, underlying mechanisms and therapeutic targeting.Frontiers in aging neuroscience · 2026Review
- Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).International journal of molecular medicine · 2025Review
- Apolipoprotein E in Alzheimer's disease: molecular insights and therapeutic opportunities.Molecular neurodegeneration · 2025Review
- The novel estrogen receptor beta agonist EGX358 andFrontiers in aging neuroscience · 2024Article
- New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease.Frontiers in neuroscience · 2024Review
- A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3.Alzheimer's research & therapy · 2023Article
- Cancer drugs with high repositioning potential for Alzheimer's disease.Expert opinion on emerging drugs · 2023Review
- Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Article
- Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE.Neurobiology of disease · 2022Article
- Lipoproteins in the Central Nervous System: From Biology to Pathobiology.Annual review of biochemistry · 2022Review
- TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.Molecular neurodegeneration · 2022Review
- ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.Neuron · 2022Review
- Remembering your A, B, C's: Alzheimer's disease and ABCA1.Acta pharmaceutica Sinica. B · 2022Review
- Small-molecule drugs development for Alzheimer's disease.Frontiers in aging neuroscience · 2022Review
- Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer's Disease and Type 2 Diabetes.ACS pharmacology & translational science · 2021Article
- Perspectives on the Role ofJournal of Alzheimer's disease reports · 2021Review
- LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express HumanFrontiers in neuroscience · 2021Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Previous data demonstrate that bexarotene (Bex), retinoid X receptor (RXR) agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer disease (AD)-transgenic mice either by increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. However, although the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If the APOE4 loss-of-function is lipidation of apoE4, then induction of ABCA1/ABCG1 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ) are highest in E4FAD hippocampus (HP) > E3FAD-HP > E4FAD cortex (CX) > E3FAD-CX, whereas levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6 months). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6 months) increased ABCA1, apoE4 lipoprotein-association/lipidation, and apoE4/Aβ complex, decreased soluble Aβ, and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG100268. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6 months) and actually increased soluble Aβ levels in E3FAD-CX and E4FAD-CX with the short-term protocol, possibly the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology, i.e. low levels of apoE4 lipoprotein association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.
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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 Socratic graph.