Alzheimer's Protective Cross-Interaction between Wild-Type and A2T Variants Alters Aβ₄₂ Dimer Structure

Whole genome sequencing has recently revealed the protective effect of a single A2T mutation in heterozygous carriers against Alzheimer's disease (AD) and age-related cognitive decline. The impact of the protective cross-interaction between the wild-type (WT) and A2T variants on the dimer structure is therefore of high interest, as the Aβ dimers are the smallest known neurotoxic species. Toward this goal, extensive atomistic replica exchange molecular dynamics simulations of the solvated WT homo- and A2T hetero- Aβ_1-42 dimers have been performed, resulting into a total of 51 μs of sampling for each system. Weakening of a set of transient, intrachain contacts formed between the central and C-terminal hydrophobic residues is observed in the heterodimeric system. The majority of the heterodimers with reduced interaction between central and C-terminal regions lack any significant secondary structure and display a weak interchain interface. Interestingly, the A2T N-terminus, particularly residue F4, is frequently engaged in tertiary and quaternary interactions with central and C-terminal hydrophobic residues in those distinct structures, leading to hydrophobic burial. This atypical involvement of the N-terminus within A2T heterodimer revealed in our simulations implies possible interference on Aβ₄₂ aggregation and toxic oligomer formation, which is consistent with experiments. In conclusion, the present study provides detailed structural insights onto A2T Aβ₄₂ heterodimer, which might provide molecular insights onto the AD protective effect of the A2T mutation in the heterozygous state.