%0 Journal Article
%T Hybrid Multifunctional Modulators Inhibit Multifaceted A¦Â Toxicity and Prevent Mitochondrial Damage
%J -
%D 2018
%R https://doi.org/10.1021/acschemneuro.8b00033
%X Amyloid beta (A¦Â) aggregation is the key trait responsible for the pathological devastation caused by Alzheimer¡¯s disease (AD). Among the various pathways of multifaceted toxicity exhibited by A¦Â aggregates in neuronal cells, generation of reactive oxygen species (ROS) by A¦Â-CuII complex and mitochondrial damage are prominent. A¦Â interferes with mitochondrial transport channels, causing mitochondrial dysfunction. Herein, we present nontoxic hybrid multifunctional modulators (HMMs, TGR86¨C88) developed by integrating the structural and functional features of the metal chelating aggregation modulator, clioquinol (Clq), and the antioxidant epigallocatechin gallate (EGCG). Detailed biophysical and docking studies show that TGR86 interacts with A¦Â and efficiently modulates both metal-dependent and metal-independent A¦Â aggregation. TGR86 complexes with CuII, arrests its redox cycle, and thereby prevents the generation of ROS. The antioxidant nature of the HMMs effectively prevents DNA damage and protein oxidation. TGR86 rescued PC12 cells from A¦Â-induced neurotoxicity by preventing the generation of ROS and foiling the interaction of toxic A¦Â species with mitochondria, thereby averting its damage. These key attributes make TGR86 a potential candidate to develop therapeutics for the multifactorial A¦Â toxicity in Alzheimer¡¯s disease
%U https://pubs.acs.org/doi/10.1021/acschemneuro.8b00033