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Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245438/ https://www.ncbi.nlm.nih.gov/pubmed/37280636 http://dx.doi.org/10.1186/s13024-023-00620-9 |
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author | Nemergut, Michal Marques, Sérgio M. Uhrik, Lukas Vanova, Tereza Nezvedova, Marketa Gadara, Darshak Chandulal Jha, Durga Tulis, Jan Novakova, Veronika Planas-Iglesias, Joan Kunka, Antonin Legrand, Anthony Hribkova, Hana Pospisilova, Veronika Sedmik, Jiri Raska, Jan Prokop, Zbynek Damborsky, Jiri Bohaciakova, Dasa Spacil, Zdenek Hernychova, Lenka Bednar, David Marek, Martin |
author_facet | Nemergut, Michal Marques, Sérgio M. Uhrik, Lukas Vanova, Tereza Nezvedova, Marketa Gadara, Darshak Chandulal Jha, Durga Tulis, Jan Novakova, Veronika Planas-Iglesias, Joan Kunka, Antonin Legrand, Anthony Hribkova, Hana Pospisilova, Veronika Sedmik, Jiri Raska, Jan Prokop, Zbynek Damborsky, Jiri Bohaciakova, Dasa Spacil, Zdenek Hernychova, Lenka Bednar, David Marek, Martin |
author_sort | Nemergut, Michal |
collection | PubMed |
description | 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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-023-00620-9. |
format | Online Article Text |
id | pubmed-10245438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-102454382023-06-08 Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate Nemergut, Michal Marques, Sérgio M. Uhrik, Lukas Vanova, Tereza Nezvedova, Marketa Gadara, Darshak Chandulal Jha, Durga Tulis, Jan Novakova, Veronika Planas-Iglesias, Joan Kunka, Antonin Legrand, Anthony Hribkova, Hana Pospisilova, Veronika Sedmik, Jiri Raska, Jan Prokop, Zbynek Damborsky, Jiri Bohaciakova, Dasa Spacil, Zdenek Hernychova, Lenka Bednar, David Marek, Martin Mol Neurodegener Research Article 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: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-023-00620-9. BioMed Central 2023-06-06 /pmc/articles/PMC10245438/ /pubmed/37280636 http://dx.doi.org/10.1186/s13024-023-00620-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Nemergut, Michal Marques, Sérgio M. Uhrik, Lukas Vanova, Tereza Nezvedova, Marketa Gadara, Darshak Chandulal Jha, Durga Tulis, Jan Novakova, Veronika Planas-Iglesias, Joan Kunka, Antonin Legrand, Anthony Hribkova, Hana Pospisilova, Veronika Sedmik, Jiri Raska, Jan Prokop, Zbynek Damborsky, Jiri Bohaciakova, Dasa Spacil, Zdenek Hernychova, Lenka Bednar, David Marek, Martin Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate |
title | Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate |
title_full | Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate |
title_fullStr | Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate |
title_full_unstemmed | Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate |
title_short | Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate |
title_sort | domino-like effect of c112r mutation on apoe4 aggregation and its reduction by alzheimer’s disease drug candidate |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245438/ https://www.ncbi.nlm.nih.gov/pubmed/37280636 http://dx.doi.org/10.1186/s13024-023-00620-9 |
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