Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure

• DOI: 10.15252/embj.2021108591
• Publication Date: 2021-11-29T10:03:34Z
• Authors: Katerina Konstant...; Patricia Guerreiro; Meine Ramakers; Nikolaos Louros; Liam D Aubrey; Bert Houben; Emiel Michiels; Matthias De Vlees...; Yulia Lampi; Luís F Ribeiro; Joris de Wit; Wei‐Feng Xue; Joost Schymkowitz; Frederic Rousseau
• Keywords: 0301 basic medicine; Biochemistry & Molecular Biology; ALPHA-SYNUCLEIN; Proteome; PROPAGATION; FORCE; 03 medical and health sciences; Humans; Protein Interaction Maps; SPECIFICITY; A-BETA; Science & Technology; Amyloid beta-Peptides; Q; toxicity; Cell Biology; Alzheimer's disease; SEQUENCE DETERMINANTS; amyloid beta; ALZHEIMERS-DISEASE; PATHOLOGY; heterotypic aggregation; HEK293 Cells; TAU; QP517; Protein Multimerization; PROTEIN AGGREGATION; Life Sciences & Biomedicine; Protein Binding

It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some 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-β structure. Here, we investigated whether Aβ amyloid assembly can be modified by heterotypic interactions between Aβ APRs and short homologous segments in otherwise unrelated human proteins. Mining existing proteomics data of Aβ plaques from AD patients revealed an enrichment in proteins that harbour such homologous sequences to the Aβ APRs, suggesting heterotypic amyloid interactions may occur in patients. We identified homologous APRs from such proteins and show that they can modify Aβ assembly kinetics, fibril morphology and deposition pattern in vitro. Moreover, we found three of these proteins upon transient expression in an Aβ reporter cell line promote Aβ amyloid aggregation. Strikingly, we did not find a bias towards heterotypic interactions in plaques from AD mouse models where Aβ self-aggregation is observed. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealized role in amyloid-deposition diseases.