Comparison of MAK33 V_L oligomers and fibrils.

<p>A) Procedure to form oligomers and fibrils. B), C) Electron micrographs of MAK33 V_L S20N oligomers (B) and fibrils (C). The scale bar denotes 200 nm. D) FTIR spectra of MAK33 V_L S20N oligomers and fibrils. The peak maxima were 1619 cm^-1 (oligomers) and 1621 cm^-1 (fibrils), respectively. The oligomer spectrum displayed an additional peak at 1697 cm^-1. E) PDSD ¹³C,¹³C-intraresidue correlations of MAK33 V_L S20N fibrils and MAK33 V_L WT oligomers. The proline spin system, which is more intense in the oligomers, is highlighted in blue.</p

Secondary structure analysis of MAK33 V_L in the fibril state.

<p>A) β-sheet propensity calculated with TALOS+ [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181799#pone.0181799.ref032" target="_blank">32</a>]. B) Sequence and secondary structure elements of the native V_L fold. Green and red bars indicate β-strands and CDRs of the native structure, respectively. Red arrows below the sequence indicate β-strands in the fibril state. The expansion shows the assigned atoms in the aggregated state.</p

¹³C,¹⁵N correlations of MAK33 V_L S20N fibrils.

<p>A) N(CA)CX spectrum of a u-¹³C,¹⁵N labeled sample. B) NCA spectrum of a 2-¹³C-glycerole isotope labeled sample. Peak positions are identical in A) and B), indicating good reproducibility. The resolution in B) is increased due to sparse isotope labeling.</p

Comparison with AL-09, amyloid prediction algorithms and native state chemical shifts.

<p>A) Sequence alignment of MAK33 V_L S20N and AL-09 V_L: Identical residues are marked in blue. Residues assigned in MAS ssNMR spectra are indicated by bars above and below the corresponding sequence. B) Predictions of MAK33 V_L S20N amyloid propensity and experimentally observed β-strands. C) Secondary chemical shift correlation of MAK33 V_L S20N in the solid-state (fibrils, pH 2) and solution-state (native, pH 6.5) for Cα, Cβ, CO and N chemical shifts. The cross-correlation coefficients r are indicated in each plot.</p

Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer’s Disease Amyloid‑β Peptide Which Exhibit Reduced Neurotoxicity

Alzheimer’s disease is characterized by deposition of the amyloid β-peptide (Aβ) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric Aβ peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. <i>In vitro</i>, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated Aβ solution. We find that sulindac sulfide induced Aβ aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a β-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. ¹³C–¹⁹F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Aβ peptide in the aggregate