Abstract
Oligomeric amyloid-β aggregates (AβOs) effectively trigger Alzheimer's disease-related toxicity, generating great interest in understanding their structures and formation mechanisms. However, AβOs are heterogeneous and transient, making their structure and formation difficult to study. Here, we performed graph network analysis of tens of microsecond massive simulations of early amyloid-β (Aβ) aggregations at near-atomic resolution to characterize AβO structures with sizes up to 20-mers. We found that AβOs exhibit highly curvilinear, irregular shapes with occasional lateral branches, consistent with recent cryo-electron tomography experiments. We also found that Aβ40 oligomers were more likely to develop branches than Aβ42 oligomers, explaining an experimental observation that only Aβ40 was trapped in network-like aggregates and exhibited slower fibrillization kinetics. Moreover, AβO architecture dissection revealed that their curvilinear appearance is related to the local packing geometries of neighboring peptides and that Aβ40's greater branching ability originates from specific C-terminal interactions at branching interfaces. Finally, we demonstrate that whether Aβ oligomerization causes oligomers to elongate or to branch depends on the sizes and shapes of colliding aggregates. Collectively, this study provides bottom-up structural information for understanding early Aβ aggregation and AβO toxicity.