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

The self-aggregation of amyloid-beta (A beta) and tau proteins are closely implicated in Alzheimer's disease (AD). Recent evidence indicates that A beta 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 A beta (A beta(16)(-)(22)) and each of two fibril-nucleating core segments of tau (PHF6* and PHF6). Both PHF6 and PHF6* are found to co-aggregate with A beta(16)(-)(22) into beta-sheet-rich heterooligomers. Intriguingly, PHF6 and A beta(16)(-)(22) peptides formed closed beta-barrels, while PHF6* and A beta(16)(-)(22) formed open beta-barrels, implying their distinct co-aggregation property. Compared to A beta(16)(-)(22)-PHF6*, A beta(16)(-)(22)-PHF6 heterooligomers have higher beta-sheet content, and contain longer beta-strands and larger beta-sheets, indicative of stronger co-aggregation ability of PHF6 with A beta(16)(-)(22). Further analyses reveal that hydrophobic and pi-pi stacking interactions between Y310 of PHF6 and A beta(16)(-)(22) are crucial for the closed beta-barrel/larger beta-sheet formation in A beta(16)(-)(22)-PHF6 heterooligomers. These results highlight the paramount importance of PHF6 fragment, particularly Y310 residue, as a potential target for inhibiting A beta-tau co-aggregation, which could help for effective therapeutic design in mitigating A beta-tau co-aggregation related amyloidogenesis.