ABSTRACT
Abnormal aggregation and subsequent fibrillogenesis of amyloid-ß protein (Aß) can cause Alzheimer's disease (AD). Thus, the discovery of effective drugs that inhibit Aß fibrillogenesis in the brain is important for the treatment of AD. Our previous study has proven that tolcapone inhibits Aß fibrillogenesis and alleviates its cytotoxicity based on systematic in vitro and in vivo experiments. However, the severe hepatotoxicity of tolcapone seriously limits its further potential application in the treatment of AD. Herein, an inhibitory effect of a low-toxicity tolcapone derivative (Tol-D) on Aß fibrillogenesis was explored. Based on the thioflavin T fluorescence data, Tol-D inhibited Aß fibrillogenesis, and the inhibitory capacity increased with the increase of its concentrations with an IC50 of â¼8.99 µM. The results of cytotoxicity showed that Tol-D greatly reduced the cytotoxicity induced by Aß42 fibrillogenesis. Moreover, Tol-D significantly alleviated Aß deposits and extended the lifespan of nematodes in transgenic Caenorhabditis elegans models. Finally, Tol-D significantly relieved Aß-induced cognitive dysfunction in mice experiments. Overall, the above experimental results indicated that Tol-D is a novel candidate therapeutic compound for the treatment of AD.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Cognitive Dysfunction/metabolism , Mice , Peptide Fragments , Tolcapone/therapeutic useABSTRACT
Misfolding and the subsequent self-assembly of amyloid-ß protein (Aß) is very important in the occurrence of Alzheimer's disease (AD). Thus, inhibition of Aß aggregation is currently an effective method to alleviate and treat AD. Herein, a carboxylated single-walled carbon nanotube (SWCNT-COOH) was rationally designed based on the hydrophobic binding-electrostatic repulsion (HyBER) mechanism. The inhibitory effect of SWCNT-COOH on Aß fibrillogenesis was first studied. Based on the results of thioflavin T fluorescence and atomic force microscopy imaging assays, it was shown that SWCNT-COOH can not only effectively inhibit Aß aggregation, but also depolymerize the mature fibrils of Aß. In addition, its inhibitory action will be affected by the content of carboxyl groups. Moreover, the influence of SWCNT-COOH on cytotoxicity induced by Aß was investigated by the MTT method. It was found that SWCNT-COOH can produce an anti-Aß neuroprotective effect in vitro. Molecular dynamics simulations showed that SWCNT-COOH significantly destroyed the overall and internal structural stability of an Aß40 trimer. Moreover, SWCNT-COOH interacted strongly with the N-terminal region, turn region and C-terminal region of the Aß40 trimer via hydrogen bonds, salt bridges and π-π interactions, which triggered a large structural disturbance of the Aß40 trimer, reduced the ß-sheet content of the Aß40 trimer and led to more disorder in these regions. All the above data not only reveal the suppressive effect of SWCNT-COOH on Aß aggregation, but also reveal its inhibitory mechanism, which provides a useful clue to exploit anti-Aß drugs in the future.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Biocompatible Materials/pharmacology , Nanotubes, Carbon/chemistry , Neuroprotective Agents/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Biocompatible Materials/chemical synthesis , Biocompatible Materials/chemistry , Cell Survival/drug effects , Hydrophobic and Hydrophilic Interactions , Materials Testing , Molecular Dynamics Simulation , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , PC12 Cells , Particle Size , Protein Aggregates/drug effects , Rats , Static ElectricityABSTRACT
GV971 derived from marine acidic oligosaccharides has been used to cure Alzheimer's disease (AD). However, the molecular mechanism of its inhibition of the conformational transition of amyloid ß-proteins (Aß) is still unclear. Herein, molecular dynamics simulations were used to explore the molecular mechanism of the main GV971 components including DiM, TetraM, HexaM, and OctaM to inhibit the conformational conversion of the Aß42 monomer. It is found that the GV971 components inhibit the conformational transition from α-helix to ß-sheet and the hydrophobic collapse of the Aß42 monomer. In addition, the binding energy analysis implies that both electrostatic and van der Waals interactions are beneficial to the binding of GV971 components to the Aß42 monomer. Among them, electrostatic interactions occupy the dominant position. Moreover, the GV971 components mainly interact directly with the charged residues D1, R5, K16, and K28 by forming salt bridges and hydrogen bonds, which specifically bind to the N-terminal region of Aß42.
