Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer's Disease Drug Candidate

Nemergut, M.; Marques, S. M.; Uhrik, L.; Vanova, T.; Nezvedova, M.; Gadara, D. C.; Jha, D.; Tulis, J.; Novakova, V.; Iglesias-Planas, 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.

doi:10.1101/2022.10.09.511473

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bioRxiv · 10.1101/2022.10.09.511473

Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer's Disease Drug Candidate

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Abstract

BackgroundApolipoprotein E (ApoE) {varepsilon}4 genotype is the most prevalent risk factor for late-onset Alzheimers 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 {varepsilon}3/{varepsilon}3 and {varepsilon}4/{varepsilon}4 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 [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 {varepsilon}4/{varepsilon}4 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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Nemergut, M., Marques, S. M., Uhrik, L., Vanova, T., Nezvedova, M., Gadara, D. C., Jha, D., Tulis, J., Novakova, V., Iglesias-Planas, 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.. 2022-10-09. Domino-like Effect of C112R Mutation on APOE4 Aggregation and Its Suppression by Alzheimer's Disease Drug Candidate. https://doi.org/10.1101/2022.10.09.511473

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