A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms

Year: 2015

Type: article

Abstract: Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5b10043

Authors: Jeffrey S. Derrick, Richard A. Kerr, Younwoo Nam, Shin Bi Oh, Hyuck Jin Lee, Kaylin G. Earnest, Nayoung Suh, Kristy L. Peck, Mehmet Ozbil, Kyle J. Korshavn, Ayyalusamy Ramamoorthy, Rajeev Prabhakar, Edward J. Merino, Jason Shearer, Joo-Yong Lee, Brandon T. Ruotolo, Mi Hee Lim

Institutions: Ulsan National Institute of Science and Technology, University of Michigan, Asan Medical Center, University of Cincinnati, University of Nevada, Reno, University of Miami, University of Ulsan

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Science Foundation, U.S. Department of Energy, National Research Foundation, Ulsan National Institute of Science and Technology, Ministry of Science, ICT and Future Planning, National Research Foundation of Korea, Asan Institute for Life Sciences, Asan Medical Center, Daegu Gyeongbuk Institute of Science and Technology, National Institutes of Health, Office of Science, Medical School, University of Michigan, National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources, Division of Chemistry, National Center for Advancing Translational Sciences, Basic Energy Sciences, Brookhaven National Laboratory

OpenAlex ID: W2222001997