Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.

ABSTRACT: Soluble amyloid beta assemblies (A? 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 A? n toxicity is at best scant. Here, we comparatively analyze A? 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 A? 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 ?-sheet rich A? n into the membrane, compromising membrane integrity. These previously elusive toxic surfaces mapped here provide an unprecedented foundation to establish structure-toxicity relationships of A? assemblies.

SUBMITTER: Ahmed R 

PROVIDER: S-EPMC6585597 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature