Natural Compounds as Inhibitors of Aβ Peptide Aggregation: Chemical Requirements and Molecular Mechanisms

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-β (Aβ) peptides are recognized as the main cause of AD progression, leading to the formation of toxic Aβ oligomers and to the deposition of β-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with Aβ aggregation by direct interaction with Aβ peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the Aβ regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and β1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

“…Second, these compounds are small molecules and produce insufficient steric effects to disrupt Aβ aggregation. Third, the protein–protein binding regions are relatively featureless to small molecules without specific pockets or grooves [ 147 , 148 ].…”

“…Some compounds with binding epitopes or planar hydrophobic structures increase Aβ aggregation inhibitory activities, including tanshinone and uncarinic acid C. A few compounds, namely, epigallocatechin gallate (EGCG) and resveratrol, interact with the toxicity determinants of Aβ, the N-terminus and β1-turn regions. Epigallocatechin gallate (EGCG), oleuropein aglicone (OleA), and quercetin are potential therapeutic compounds for AD [ 147 ].…”

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

“…An array of compounds has been identified as potential inhibitors or modulators of protein misfolding and aggregation. Notably, most of the promising molecules that have been identified target misfolded Aβ and α-syn; these molecules appear to bind to oligomers and larger aggregates such as amyloid plaques [146,147]. Such compounds can be categorized into three main types: antibodies, peptide inhibitors, and small molecule inhibitors such as NPs [132].…”

Autoxidation Enhances Anti-Amyloid Potential of Flavone Derivatives

“…While primary nucleation causes the formation of nuclei that eventually grow into fibril aggregates, secondary nucleation is shown to be the main source of more cytotoxic oligomeric species that cause direct neurotoxicity [ 13 , 14 , 15 ]. For that reason, it is beneficial to find an anti-amyloidogenic compound that prevents primary and secondary nucleation as well as elongation processes [ 16 ].…”

“…Flavones are abundant in nature and found in a variety of herbs, fruits, vegetables, and spices [ 17 ]. This group of natural anti-oxidants has been reported to possess anti-amyloid characteristics, exhibit neuroprotective, anti-inflammatory, and anti-microbial properties [ 16 , 18 ]. In addition, flavone derivatives have shown positive effects when treating diabetes, cancer, malaria, asthma, and cardiovascular system diseases [ 19 ].…”