Aβ(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage

Ciudad, S.; Puig, E.; Botzanowski, T.; Meigooni, M.; Arango, A. S.; Do, J.; Mayzel, M.; Bayoumi, M.; Chaignepain, S.; Maglia, G.; Cianferani, S.; Orekhov, V.; Tajkhorshid, E.; Bardiaux, B.; Carulla, N.

doi:10.1101/759472

bioRxiv · 10.1101/759472

Aβ(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage

Ciudad, S.·Puig, E.·Botzanowski, T.·Meigooni, M.·Arango, A. S.·Do, J.·Mayzel, M.·Bayoumi, M.·Chaignepain, S.·Maglia, G.·Cianferani, S.·Orekhov, V.·Tajkhorshid, E.·Bardiaux, B.·Carulla, N.

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Abstract

The formation of amyloid-beta (A{beta}) oligomer pores in the membrane of neurons has been proposed as the means to explain neurotoxicity in Alzheimers disease (AD). It is therefore critical to characterize A{beta} oligomer samples in membrane-mimicking environments. Here we present the first three-dimensional structure of an A{beta} oligomer formed in dodecyl phosphocholine (DPC) micelles, namely an A{beta}(1-42) tetramer. It comprises a {beta}-sheet core made of six {beta}-strands, connected by only two {beta}-turns. The two faces of the {beta}-sheet core are hydrophobic and surrounded by the membrane-mimicking environment. In contrast, the edges of the core are hydrophilic and are solvent-exposed. By increasing the concentration of A{beta}(1-42), we prepared a sample enriched in A{beta}(1-42) octamers, formed by two A{beta}(1-42) tetramers facing each other forming a {beta}-sandwich structure. Notably, samples enriched in A{beta}(1-42) tetramers and octamers are both active in lipid bilayers and exhibit the same types of pore-like behaviour, but they show different occurrence rates. Remarkably, molecular dynamics simulations showed a new mechanism of membrane disruption in which water and ion permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core {beta}-sheets edges of the A{beta}(1-42) tetramers and octamers.

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Ciudad, S., Puig, E., Botzanowski, T., Meigooni, M., Arango, A. S., Do, J., Mayzel, M., Bayoumi, M., Chaignepain, S., Maglia, G., Cianferani, S., Orekhov, V., Tajkhorshid, E., Bardiaux, B., Carulla, N.. 2019-09-12. Aβ(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage. https://doi.org/10.1101/759472

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