Dynamic-Inspired Perspective on the Molecular Inhibitor of Tau Aggregation by Glucose Gallates Based on Human Neurons

Abstract

A molecular inhibitor of tau protein aggregation offers an attractive therapeutic possibility as disease-modifying treatment of Alzheimer’s disease. However, the ineffectiveness as well as adjoint toxicity due to superficial understanding of the inhibition mechanism has hindered drug development. Conventional approaches for screening drug ligands rely on compatible docking with the well-defined structure of a protein receptor. Therefore, the design of tau aggregation inhibitors has been inevitably hindered by the unstructured, highly dynamic nature of the tau protein. This paper suggested a new strategy for reducing tau aggregation through a dynamic process of conformational isomerization. A group of glucose gallate derivatives were selected as tau aggregation inhibitors. These star-shaped molecules have a biocompatible glucose core surrounded by several gallic acid polyphenol arms, which can bind to peptide chains at different sites, probably through hydrogen bonds and π–π stacking. Theoretically, by elevating the saddle point on the potential energy surfaces (PES) of proteins, the barrier in the dynamic pathway of peptide isomerization, glucose gallates effectively inhibit tau aggregation through a dynamic mechanism. A tau cell model based on human neurons was constructed. For the first time, we confirmed that the moderate thermodynamic binding of the molecular ligand to the tau peptide chain can not only prevent the isomerization of the peptide chain leading to aggregation but also avoid toxicity resulting from the dissociation of tau from microtubules.

Molecular Deformation Is a Key Factor in Screening Aggregation Inhibitor for Intrinsically Disordered Protein Tau

“…The human neuroblastoma SK-N-SH cells infected by tau aggregates provide a reliable and effective cell model for the study of the tau self-aggregation mechanism. 18 Figure 7 demonstrates the survival rates of tauinfected SK-N-SH cells exposed to the synthetic compounds (IPP1−IPP4) at different concentrations for 24 h. The cell viability of SK-N-SH was assessed using a cell counting kit-8 (CCK-8) assay. 48 It could be seen that the cell survival rate was still higher than 70% when the concentration of IPP1 reached 30 μM.…”

Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases

“… 40 Also, gallic acid derivatives such as glucose gallates prevent the isomerization and aggregation of the tau peptide, a hallmark of AD, and promote the dissociation of tau from microtubules. 41 …”

“…The multifaceted neuroprotective activities of gallic acid in different preclinical AD and PD models have been recently reviewed by Shabani et al In addition, this hydroxybenzoic acid has been efficiently exploited to counteract both the glutamate-induced neurotoxicity in primary rat cortex neurons and the 6-OHDA-induced apoptosis in human dopaminergic neural-like cells . Also, gallic acid derivatives such as glucose gallates prevent the isomerization and aggregation of the tau peptide, a hallmark of AD, and promote the dissociation of tau from microtubules …”

“…40 Also, gallic acid derivatives such as glucose gallates prevent the isomerization and aggregation of the tau peptide, a hallmark of AD, and promote the dissociation of tau from microtubules. 41 Another important group is represented by hydroxycinnamic acids, which are the most widely distributed phenolic acids in plants. They are hydroxylated compounds derived from cinnamic acid, a compound that can be obtained from cinnamon oil and balsams like storax.…”

Cathepsin L-containing exosomes from α-synuclein-activated microglia induce neurotoxicity through the P2X7 receptor

“…The procedures for protein oligomers negative-staining were established by TEM following our previously described methods with little modification 63,64 . Briefly, 5-10 μl of each sample was dropped on a carbon support membrane, followed by dropwise addition of 5-10 μl of 1% uranyl acetate.…”