Toward a Rational Design to Regulate β-Amyloid Fibrillation for Alzheimer’s Disease Treatment

Abstract

The last decades have witnessed a growing global burden of Alzheimer's disease (AD). Evidence indicates that the onset and progression of AD is associated with β-amyloid (Aβ) peptide fibrillation. As such, there is a strong passion with discovering potent Aβ fibrillation inhibitors that can be developed into anti-amyloiddogenic agents for AD treatment. Current challenges that have arisen with this development involve with Aβ oligomer toxicity suppression and Blood Brain Barrier penetration capability. Considering most natural or biological events, one would observe that there is usually a "seed" to direct natural materials to assemble in response to a certain stimulation. Inspired by this, several materials or compounds, including nanoparticle, peptide or peptide mimics, and organic molecules, have been designed for the purpose of redirecting or impeding Aβ aggregation. Achieving these tasks requires comprehensive understanding on (1) initial Aβ assembly into insoluble deposits, (2) main concerns with fibrillation inhibition, and (3) current major methodologies to disrupt the aggregation. Herein, the objective of this review is to address these three areas, and enable the pathway for a promising therapeutic agent design for AD treatment.

Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1–40) Fibrils

“…The most common fibrils are Aβ(1–40) and Aβ(1–42), which are composed of 40 and 42 amino acids, respectively, and are characterized by β-strand units aligned perpendicularly to the main fibril axis [ 2 ]. Destabilization and clearance of amyloid aggregates by small molecules is one of the promising approaches towards the development of AD therapies [ 3 ].…”

Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1-40) Fibrils

“…The solvation energy, Gsolvation, is calculated as follows: (4) Where the non-polar solvation term, Gsurf, is approximated on the solvent-accessible-surface area (SASA) derived from the Shrake-Rupley numerical method [45] (5) with γ=0.0072kcal/mol Å 2 and β=0 [46].…”

“…The most common fibrils are Aβ and Aβ that are composed by 40 and 42 amino acids, respectively, and are characterized by β-strand units aligned perpendicular to the main fibril axis [2]. Destabilization and clearance of amyloid aggregates by small molecules is one of the promising approaches towards the development of AD therapies [4].…”

Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer’s Disease

“…For instance, BuChE inhibitors could recover cholinergic activity through restoring the AChE/BuChE activity ratios, as shown in a healthy brain [ 8 ], and BuChE may play a role in AD plaque due to its contribution to a subpopulation of Aβ plaques maturation by immunostaining analysis of AD brain tissues [ 9 ]. Nevertheless, many studies have showed that both ChEs could facilitate amyloid fibril formation to yield stable ChE-Aβ complexes, which are more toxic than a single Aβ peptide [ 10 , 11 ]. The complex of AChE, through interaction with Aβ, promotes amyloid fibril formation through a spanning hydrophobic sequence exposed on the surface of AChE, which is close to the peripheral anionic binding site (PAS) and interacts with liposomes.…”