Natural Compounds against Alzheimer’s Disease: Molecular Recognition of Aβ1–42 Peptide by Salvia sclareoides Extract and its Major Component, Rosmarinic Acid, as Investigated by NMR

Abstract

Amyloid peptides, Aβ1-40 and Aβ1-42, represent major molecular targets to develop potential drugs and diagnostic tools for Alzheimer's Disease (AD). In fact, oligomeric and fibrillar aggregates generated by these peptides are amongst the principal components of amyloid plaques found post mortem in patients suffering from AD. Rosmarinic acid has been demonstrated to be effective in preventing the aggregation of amyloid peptides in vitro and to delay the progression of the disease in animal models. Nevertheless, no information is available about its molecular mechanism of action. Herein, we report the NMR characterization of the interaction of Salvia sclareoides extract and that of its major component, rosmarinic acid, with Aβ1-42 peptide, whose oligomers have been described as the most toxic Aβ species in vivo. Our data shed light on the structural determinants of rosmarinic acid-Aβ1-42 oligomers interaction, thus allowing the elucidation of its mechanism of action. They also provide important information for the rational design of new compounds with higher affinity for Aβ peptides to generate new anti-amyloidogenic molecules and/or molecular tools for the specific targeting of amyloid aggregates in vivo. In addition, we identified methyl caffeate, another natural compound present in different plants and human diet, as a good ligand of Aβ1-42 oligomers, which also shows anti-amyloidogenic activity. Finally, we demonstrated the possibility to exploit STD-NMR and trNOESY experiments to screen extracts from natural sources for the presence of Aβ peptide ligands.

Interaction and reactivity of synthetic aminoisoflavones with metal-free and metal-associated amyloid-β

“…42 The normalized signal strengths (STD/STD reference) corresponding to each ligand atom are proportional to its proximity to the amyloid fibril, allowing an atomic-level map of the binding interactions from the ligand to the Aβ fibril to be made. 12 p ,41 The results from the STD NMR experiments indicate that both 1 and 4 interact fairly strongly (mM to μM dissociation constant) with the fibril to elicit a relatively strong STD signal (approximately 4.5% (for 1 ) and 5.9% (for 4 ) of the reference signal at a 3 sec saturation power of 50 dB, similar in magnitude to previous results with other catechols 41 ). The STD results also suggest that 1 and 4 bind similarly to the Aβ fibril (Fig.…”

“…To probe these possible interactions, we employed saturation transfer difference (STD) NMR experiments to map the regions of the ligand which bind preformed fibrils of Aβ 40 (Fig. 8) 12 p ,41 and to visualize the potential contacts of 4 with Aβ fibrils, flexible ligand docking studies were employed with the solid state NMR structure of metal-free Aβ 40 (PDB 2LMN and 2LMO) (Figs. 8c, S9, and S10).…”

Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease

“…STD experiments were acquired with a train of 60 dB Gaussian-shaped pulses of 50 ms duration at centered at either −2.0 ppm (on resonance 63–65 ) or 100 ppm (off resonance) with a total saturation time of 3 s on a Bruker 500 MHz (metal-free samples) or 900 MHz spectrometer (Zn( ii ) samples). 66 A total of 2048 transients with a 2 s recycle delay were collected for all spectra. Chemical shifts are referenced to water due to the potential interaction of Aβ40 with the chemical shift standard sodium 4,4-dimethyl-4-silapentane-1-sulfonate (DSS).…”

Brazilin inhibits fibrillogenesis of human islet amyloid polypeptide, disassembles mature fibrils, and alleviates cytotoxicity

“…18,19 Among these, small organic molecules have received special interest because of their high permeability through the blood-brain barrier and potentially low cytotoxicity. 20 Several natural compounds have been found to prevent hIAPP brillization or to transform the mature brils into unstructured, off-pathway aggregates. 8,21,22 For example, Chen et al 23 have found that the brillation and aggregation of hIAPP is affected by trehalose in a dose-dependent manner.…”