Fig. 5. Proposed model for the molecular determinants of Aβ assembly toxicity. (a) Toxic Aβn (canonical Aβn) exhibit significant solvent exposure of hydrophobic surfaces (yellow glow surrounding Aβn). Exposed hydrophobic surfaces facilitate the colocalization, interaction and subsequent insertion of Aβn into the membrane. (b) Membrane-embedded Aβn adopt both laminated and non-laminated β-sheets, indicating that under our experimental conditions the non-laminated β-sheet signature is the minimum structural feature required for membrane insertion and induction of toxicity. (c) Toxic vs. non-toxic Aβn exhibit unique regiospecific differences in the recognition of Aβ monomers within a membrane environment. Relative to canonical Aβn (black), EC- (green) and EGCG-remodeled Aβn (maroon) exhibit progressive engagement of contacts with Aβ monomers at the N-terminus and disengagement at the β1-turn region, following the same ranking as their measured toxicities. In contrast, for the β2 region no correlation is observed between toxicity and Aβn monomer recognition. Relevant experimental techniques are indicated in parenthesis. (d) Mapping on the structure of Aβ40 fibrils57 (PDB code: ; 2LMN) the Aβ residues in cluster 1 (Fig. 4b and c). The N-terminal and β1-turn residues that correlate with toxicity (blue) are found in the external regions of the Aβ fibril structure. In contrast, β2 is involved in the lamination of multiple β-sheet layers and is largely inaccessible (Table S2†), explaining its ancillary role in toxicity.
