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Cited by 30Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtein Structure and Dynamics

Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate

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Nemergut, Michal, Marques, Sérgio M., Uhrik, Lukas, Vanova, Tereza, Nezvedova, Marketa, Gadara, Darshak Chandulal, Jha, Durga, Tulis, Jan +15 more·2023·Molecular Neurodegeneration
DOI 10.1186/s13024-023-00620-9PMC PMC10245438
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Abstract

Background: Apolipoprotein 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. Methods: Here, 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. Results: We 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. Conclusions: Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing. Graphic Abstract:

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  • Lipid-free ApoE readily self-associates through hydrophobic interactions, forming oligomers and aggregates that complicate thermal stability measurements.

    “Lipid-free ApoE readily self-associates through hydrophobic interactions, forming oligomers and aggregates that complicate thermal stability measurements 40,41 .”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [41]

    The Background reports that lipid-free ApoE forms monomers, dimers, tetramers and octamers, and the Results link self-association to aggregation. But the Results describe the dimer interactions as primarily electrostatic, not hydrophobic. The Methods describe measuring thermal unfolding and aggregation together, but do not say aggregation complicates thermal-stability measurements; no page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Thermal stability may be a particularly sensitive indicator of structural perturbation in the helical bundle and domain-domain interaction regions.

    “suggests that thermal stability may be a particularly sensitive indicator of structural perturbation in these regions 22,24,33,41,51 .”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [41]

    The Discussion (page unavailable) links ApoE4’s altered intradomain interactions and H3-helix conformation to greater susceptibility to thermal denaturation than ApoE3 and ApoE2. The Methods describe measuring thermal unfolding. The paper does not establish that thermal stability is a particularly sensitive indicator of perturbations in both the helical bundle and domain–domain interaction regions. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Lipid-free ApoE readily self-associates through hydrophobic interactions.

    “Lipid-free ApoE readily self-associates through hydrophobic interactions, and this aggregation-prone behavior can complicate the interpretation of thermal stability data 41,63 .”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [41]

    The Discussion (page not provided) proposes dimers as basic units of lipid-free ApoE aggregates, supporting self-association. But the Results section on the self-association interface (page not provided) says the modeled dimer interactions were formed primarily by electrostatic contacts, not hydrophobic interactions. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The aggregation-prone behavior of ApoE can complicate the interpretation of thermal stability data.

    “Lipid-free ApoE readily self-associates through hydrophobic interactions, and this aggregation-prone behavior can complicate the interpretation of thermal stability data 41,63 .”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [41]

    The Background describes lipid-free ApoE as self-associating, and the Results report greater aggregation of ApoE4 than ApoE3. The Methods say the thermal-denaturation assay monitored unfolding and aggregation separately, but our copy does not say that aggregation complicates interpretation of thermal stability data. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The R61T mutant, which is predicted to disrupt domain interaction without altering the C-terminal sequence, normalizes signal in this assay to ApoE3 levels, providing mechanistic evidence that the N-terminal domain interaction of ApoE4 impacts self-association.

    “The observation that the mutant R61T, which is predicted to disrupt domain interaction without altering the C-terminal sequence, normalizes signal in this assay to ApoE3 levels provides mechanistic evidence that while the C-terminal domain of ApoE is undoubtedly crucial for ApoE oligomerization, the N-terminal domain interaction of ApoE4 impacts self-association (11,12,24,25).”

    From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [25]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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Cited by

Sorted by citations

Authors
Nemergut, M., Marques, S. M., Uhrik, L., Vanova, T., Nezvedova, M., Gadara, D. C., Jha, D., Tulis, J., Novakova, V., Planas-Iglesias, J., Kunka, A., Legrand, A., Hribkova, H., Pospisilova, V., Sedmik, J., Raska, J., Prokop, Z., Damborsky, J., Bohaciakova, D., Spacil, Z., Hernychova, L., Bednar, D., & Marek, M.
Affiliations
  • University of Pavol Jozef Šafárik (SK)
  • Masaryk University (CZ)
Corresponding author
Marek, Martin
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2023-06-06
Volume
18
Issue
1
Pages
38-38
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-023-00620-9
PMC
PMC10245438
OpenAlex
W4379536640
Cited by
30
References
18
Citations by year
2026: 12 · 2025: 9 · 2024: 6 · 2023: 3
FWCI
5.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • Grantová Agentura České Republiky (22-09853S)
  • European Union’s Horizon Europe (101087124)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
APOE ε4, protein aggregation, Alzheimer's disease, tramiprosate, brain organoids, APOE3, protein conformational change, cholesterol esters, cholesterol storage, druggable targets, neurodegeneration
MeSH terms
Alzheimer Disease, Apolipoproteins E, Humans, Mutation, Taurine, Apolipoprotein E3, Apolipoprotein E4

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