Heterotypic Aβ interactions facilitate amyloid assembly and modify amyloid structure

Konstantoulea, K.; Guerreiro, P.; Ramakers, M.; Louros, N.; Aubrey, L.; Houben, B.; Michiels, E.; De Vleeschouwer, M.; Lampi, Y.; Ribeiro, L.; de Wit, J.; Xue, W.-F.; Schymkowitz, J.; Rousseau, F.

doi:10.1101/2021.04.28.441786

bioRxiv · 10.1101/2021.04.28.441786

Heterotypic Aβ interactions facilitate amyloid assembly and modify amyloid structure

Konstantoulea, K.·Guerreiro, P.·Ramakers, M.·Louros, N.·Aubrey, L.·Houben, B.·Michiels, E.·De Vleeschouwer, M.·Lampi, Y.·Ribeiro, L.·de Wit, J.·Xue, W.-F.·Schymkowitz, J.·Rousseau, F.

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Abstract

It is still unclear why pathological amyloid deposition initiates in specific brain regions, nor why specific cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-{beta} structure. Here we investigated whether A{beta} amyloid assembly can be modified by heterotypic interactions between A{beta} APRs and short homologous segments in otherwise unrelated human proteins. We identified heterotypic interactions that accelerate A{beta} assembly, modify fibril morphology and affect its pattern of deposition in vitro. Moreover, we found that co-expression of these proteins in an A{beta} reporter cell line promotes A{beta} amyloid aggregation. Importantly, reanalysis of proteomics data of A{beta} plaques from AD patients revealed an enrichment in proteins that share homologous sequences to the A{beta} APRs, suggesting heterotypic amyloid interactions may occur in patients. Strikingly, we did not find such a bias in plaques from overexpression models in mouse. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealised role in amyloid-deposition diseases.

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Konstantoulea, K., Guerreiro, P., Ramakers, M., Louros, N., Aubrey, L., Houben, B., Michiels, E., De Vleeschouwer, M., Lampi, Y., Ribeiro, L., de Wit, J., Xue, W.-F., Schymkowitz, J., Rousseau, F.. 2021-04-30. Heterotypic Aβ interactions facilitate amyloid assembly and modify amyloid structure. https://doi.org/10.1101/2021.04.28.441786

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