RESUMEN
The accumulation of fibrillar amyloid-ß (Aß) aggregates in the brain, predominantly comprising 40- and 42-residue amyloid-ß (Aß40 and Aß42), is a major pathological hallmark of Alzheimer's disease (AD). Aß40 and Aß42 naturally coexist in the brain under normal physiological conditions, and their interplay is generally considered to be a critical factor in the progression of AD. In addition to forming homogeneous oligomers and fibrils, Aß40 and Aß42 are also reported to co-assemble into hetero-oligomers and interlaced mixed fibrils, as evidenced by solid-state nuclear magnetic resonance spectroscopy (NMR), high molecular weight mass spectrometry and cross-seeding experiments. However, the exact molecular mechanisms underlying these processes remain unclear. In this study, we have used a recently resolved structurally uniform 1:1 mixture of Aß40/Aß42 interlaced mixed fibril as a prototype to gain insights into the molecular-level interactions between Aß40 and Aß42. We employed fully atomistic molecular dynamics simulation and compared the results with a homogeneous U-shaped Aß40 fibrillar model. Our simulations using two different force fields provide conclusive evidence that the Aß40/Aß42 interlaced mixed fibril is energetically more favorable than the homogeneous Aß40 fibrillar model. Furthermore, we also show that the increase in stability observed in the mixed model stems primarily from the packing interfaces and the stacking interfaces between C-termini. Our simulation results provide valuable mechanistic insights that are not readily accessible in experiment and could have significant implications for both the pathogenesis of AD and the development of current therapeutic strategies.Communicated by Ramaswamy H. Sarma.
