Atomic resolution map of the soluble amyloid beta assembly toxic surfaces

Abstract

Soluble amyloid beta assemblies (Aβ_n) are neurotoxic and play a central role in the early phases of the pathogenesis cascade leading to Alzheimer's disease. However, the current knowledge about the molecular determinants of Aβ_n toxicity is at best scant. Here, we comparatively analyze Aβ_n prepared in the absence or presence of a catechin library that modulates cellular toxicity. By combining solution NMR with dynamic light scattering, fluorescence spectroscopy, electron microscopy, wide-angle X-ray diffraction and cell viability assays, we identify a cluster of unique molecular signatures that distinguish toxic vs. nontoxic Aβ assemblies. These include the exposure of a hydrophobic surface spanning residues 17–28 and the concurrent shielding of the highly charged N-terminus. We show that the combination of these two dichotomous structural transitions promotes the colocalization and insertion of β-sheet rich Aβ_n into the membrane, compromising membrane integrity. These previously elusive toxic surfaces mapped here provide an unprecedented foundation to establish structure-toxicity relationships of Aβ assemblies.