Structure of amyloid β25-35 in lipid environment and cholesterol-dependent membrane pore formation

Scientific Reports
Nabin KandelSuren A Tatulian

Abstract

The amyloid β (Aβ) peptide and its shorter variants, including a highly cytotoxic Aβ25-35 peptide, exert their neurotoxic effect during Alzheimer's disease by various mechanisms, including cellular membrane permeabilization. The intrinsic polymorphism of Aβ has prevented the identification of the molecular basis of Aβ pore formation by direct structural methods, and computational studies have led to highly divergent pore models. Here, we have employed a set of biophysical techniques to directly monitor Ca2+-transporting Aβ25-35 pores in lipid membranes, to quantitatively characterize pore formation, and to identify the key structural features of the pore. Moreover, the effect of membrane cholesterol on pore formation and the structure of Aβ25-35 has been elucidated. The data suggest that the membrane-embedded peptide forms 6- or 8-stranded β-barrel like structures. The 8-stranded barrels may conduct Ca2+ ions through an inner cavity, whereas the tightly packed 6-stranded barrels need to assemble into supramolecular structures to form a central pore. Cholesterol affects Aβ25-35 pore formation by a dual mechanism, i.e., by direct interaction with the peptide and by affecting membrane structure. Collectively, our data illuminate t...Continue Reading

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Citations

Aug 28, 2020·The European Journal of Neuroscience·Nikita Patil Samant, Girdhari Lal Gupta
May 11, 2019·Scientific Reports·Amy K Smith, Dmitri K Klimov
Jun 3, 2021·Cells·Stefania MerighiDavide Ferrari
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Methods Mentioned

BETA
light scattering
static light scattering
fluorescence spectroscopy

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