ArticleMolecular neurodegeneration2023
Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate.
Article in Molecular neurodegeneration, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Mapping the Cerebral Organoid Landscape: A Systematic Review of Preclinical 3D Models in Neuroscience.Advanced healthcare materials · 2026Pooled it
- A targeted lipidomics workflow for high-throughput phenotyping and mechanism-based in vitro hepatotoxicity studies.Toxicology in vitro : an international journal published in association with BIBRA · 2026Article
- Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.Neural regeneration research · 2026Article
- Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.Frontiers in cell and developmental biology · 2026Review
- Evaluating the cognitive efficacy of marine-derived drugs in Alzheimer's disease: A systematic review and Bayesian network meta-analysis.Therapeutic advances in neurological disorders · 2026Article
- APOE Genotype Difference in the Biphasic Modulation of Amyloid-β Aggregation by Direct Binding and Lowering the Nucleation Barrier.Biomacromolecules · 2025Article
- HYPOTHESIS: Lipid-protecting disulfide bridges are the missing molecular link between ApoE4 and sporadic Alzheimer's disease in humans.Prostaglandins, leukotrienes, and essential fatty acids · 2025Article
- Discovery of Isobavachin, a Natural Flavonoid, as an Apolipoprotein E4 (ApoE4) Structure Corrector for Alzheimer's Disease.Molecules (Basel, Switzerland) · 2025Article
- Multifaceted roles of APOE in Alzheimer disease.Nature reviews. Neurology · 2024Review
- CoVAMPnet: Comparative Markov State Analysis for Studying Effects of Drug Candidates on Disordered Biomolecules.JACS Au · 2024Article
- Biochemical evidence for conformational variants in the anti-viral and pro-metastatic protein IFITM1.Biological chemistry · 2024Article
- High-Throughput Microbore LC-MS Lipidomics to Investigate APOE Phenotypes.Analytical chemistry · 2024Article
Corrections and comments
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Authors and funding
23 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundApolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.
methodsHere, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.
resultsWe found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.
conclusionsOur results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.
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