Characterization of Alzheimer's Protective and Causative Amyloid-beta Variants Using a Combination of Simulations and Experiments

The aggregation of amyloid-beta (A$\beta )$ peptides plays a crucial role in the etiology of Alzheimer's disease (AD). Recently, it has been reported that an A2T mutation in A$\beta $ can protect from AD. Interestingly, an A2V mutation has been also found to offer protection against AD in the heterozygous state. Structural characterization of these natural A$\beta $ variants thus offers an intriguing approach to understand the molecular mechanism of AD. Toward this goal, we have characterized the conformational landscapes of the intrinsically disordered WT, A2V, and A2T A$\beta $1-42 variant monomers and dimers by using extensive atomistic molecular dynamics (MD) simulations. Simulations reveal markedly different secondary and tertiary structure at the central and C-terminal hydrophobic regions of the peptide, which play a crucial role in A$\beta $ aggregation and related toxicity. For example, an enhanced double $\beta $-hairpin formation was observed in A2V monomer. In contrast, the A2T mutation enhances disorder of the conformational ensemble due to formation of atypical long-range interactions. These structural insights obtained from simulations allow understanding of the differential aggregation, oligomer morphology, and LTP inhibition of the variants observed in the experiments and offer a path toward designing and testing aggregation inhibitors.