Structural insights into the co-aggregation of Aβ and tau amyloid core peptides: Revealing potential pathological heterooligomers by simulations.

The self-aggregation of amyloid-β (Aβ) and tau proteins are closely implicated in Alzheimer's disease (AD). Recent evidence indicates that Aβ and tau proteins can cross-interact to form co-aggregates, which aggravates the development of AD. However, their transient heterooligomer conformations and co-aggregation molecular mechanisms are largely unknown. Herein, we utilize replica exchange molecular dynamics simulations to investigate the conformational ensembles formed by the central hydrophobic core of Aβ (Aβ) and each of two fibril-nucleating core segments of tau (PHF6* and PHF6). Both PHF6 and PHF6* are found to co-aggregate with Aβ into β-sheet-rich heterooligomers. Intriguingly, PHF6 and Aβ peptides formed closed β-barrels, while PHF6* and Aβ formed open β-barrels, implying their distinct co-aggregation property. Compared to Aβ-PHF6*, Aβ-PHF6 heterooligomers have higher β-sheet content, and contain longer β-strands and larger β-sheets, indicative of stronger co-aggregation ability of PHF6 with Aβ. Further analyses reveal that hydrophobic and π-π stacking interactions between Y310 of PHF6 and Aβ are crucial for the closed β-barrel/larger β-sheet formation in Aβ-PHF6 heterooligomers. These results highlight the paramount importance of PHF6 fragment, particularly Y310 residue, as a potential target for inhibiting Aβ-tau co-aggregation, which could help for effective therapeutic design in mitigating Aβ-tau co-aggregation related amyloidogenesis.