Impact of the Rat R5G, Y10F, and H13R Mutations on Tetrameric Aβ42 β-Barrel in a Lipid Bilayer Membrane Model

Three amino acid substitutions distinguish rat and human Aβ42 peptides and contribute to the difference in toxicity properties. Indeed, aged rodents rarely develop the characteristic lesions of Alzheimer's disease in contrast to humans. Both peptides form, however, amyloid fibrils in buffer solution, but their affinities to the membrane vary. In particular, there is experimental evidence that the rat Aβ42 peptide does not induce Ca 2+ fluxes in cells. We recently designed a tetrameric β-barrel structure and showed that this model is severely destabilized for Aβ40 human compared to its Aβ42 human counterpart, explaining the absence of ionic currents of Aβ40 in planar lipid bilayers. In this study, we asked whether our model is destabilized for the rat Aβ42 peptide by using extensive replica exchange molecular dynamics simulation in a dipalmitoylphosphatidylcholine (DPPC) lipid bilayer membrane. Our results show that the much lower propensity of aged rodents to develop Alzheimer's disease symptoms might be correlated to its tetrameric β-barrel stability in the cell membrane.