Cross-Interactions\nof Aβ Peptides Implicated\nin Alzheimer’s Disease Shape Amyloid Oligomer Structures and\nAggregation

A defining hallmark of Alzheimer’s disease (AD)\nis the synaptic\naggregation of the amyloid β (Aβ) peptide. <i>In\nvivo</i>, Aβ production results in a diverse mixture of\nvariants, of which Aβ40, Aβ42, and Aβ43 are profusely\npresent in the AD brain, and their relative abundance is recognized\nto play a role in disease onset and progression. Nonetheless, the\noccurrence of Aβ40, Aβ42, and Aβ43 hetero-oligomerization\nand the subsequent effects on Aβ aggregation remain elusive\nand were investigated here. Using thioflavin-T (ThT)-monitored aggregation\nassays and native mass spectrometry coupled to ion mobility analysis\n(IM-MS), we first show that all Aβ peptides are aggregation-competent\nand self-assemble into homo-oligomers with distinct conformational\npopulations, which are more pronounced between Aβ40 than the\nlonger variants. ThT assays were then conducted on binary mixtures\nof Aβ variants, revealing that Aβ42 and Aβ43 aggregate\nindependently from Aβ40 but significantly speed up Aβ40\nfibrillation. Aβ42 and Aβ43 were observed to aggregate\nconcurrently and mutually accelerate fibril formation, which likely\ninvolves hetero-oligomerization. Accordingly, native MS analysis revealed\npairwise oligomerization between all variants, with the formation\nof heterodimers and heterotrimers. Interestingly, IM-MS indicates\nthat hetero-oligomers containing longer Aβ variants are enriched\nin conformers with lower collision cross-sections when compared to\ntheir homo-oligomer counterparts. This suggests that Aβ42 and\nAβ43 are capable of remodeling the oligomer structure toward\na higher compaction level. Altogether, our findings provide a mechanistic\ndescription for the hetero-oligomerization of Aβ variants implicated\nin AD, contributing to rationalizing their <i>in vivo</i> proteotoxic interplay.