Alzheimer's Protective Cross-Interaction Between Wild-Type and A2T Variants Changes Aβ42 Dimer Structure

Abstract

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 smallest known neurotoxic species. Toward this goal, extensive atomistic replica exchange molecular dynamics simulations of the solvated WT homo- and A2T hetero- Aβ1-42 dimers have been performed, resulting into a total of 51 μs of sampling for each system. Simulated heterodimer reveals a striking lowering of transient interactions formed between central and C-terminal hydrophobic regions, when compared to the WT homodimer. Interestingly, the A2T N-terminus forms intra- and inter-peptide contacts with the central and C-terminal residues. 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 the AD protective effect of the A2T mutation in the heterozygous state.