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

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Authors

NEMERGUT Michal MARQUES Sérgio Manuel UHRÍK Lukáš VÁŇOVÁ Tereza NEZVEDOVÁ Markéta GADARA Darshak Chandulal JHA Durga TULIS Jan NOVÁKOVÁ Veronika PLANAS IGLESIAS Joan KUNKA Antonín LEGRAND Anthony Thomas P HŘÍBKOVÁ Hana POSPÍŠILOVÁ Veronika SEDMÍK Jiří RAŠKA Jan PROKOP Zbyněk DAMBORSKÝ Jiří BOHAČIAKOVÁ Dáša SPÁČIL Zdeněk HERNYCHOVÁ Lenka BEDNÁŘ David MAREK Martin

Year of publication 2023
Type Article in Periodical
Magazine / Source Molecular Neurodegeneration
MU Faculty or unit

Faculty of Science

Citation
Web https://doi.org/10.1186/s13024-023-00620-9
Doi http://dx.doi.org/10.1186/s13024-023-00620-9
Keywords Apolipoprotein E; Alzheimer’s disease; Neurodegeneration; Aggregation; Cerebral organoids; Molecular dynamics; HDX-MS; Protein crystallography; Proteomics; Lipidomics; Tramiprosate; 3-sulfopropanoic acid
Attached files
Description Background Apolipoprotein E (ApoE) epsilon 4 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 epsilon 3/epsilon 3 and epsilon 4/epsilon 4 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 A) 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 epsilon 4/epsilon 4 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.
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