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GMP‐1 and its analogues bind Cu 2+ and Zn 2+ and protect neurons against amyloid beta toxicity
Author(s) -
Winblad Bengt,
Pavlov Pavel F.,
Kumar Rajnish
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044510
Subject(s) - clioquinol , chemistry , thioflavin , amyloid beta , biochemistry , metallothionein , neuroprotection , neurotoxicity , alzheimer's disease , pharmacology , biophysics , toxicity , biology , medicine , peptide , disease , organic chemistry , gene
Background Alzheimer disease (AD) is a complex multifactorial disease representing >60 % cases of dementia with no disease modifying therapies available in clinics largely due to its poorly understood pathology. Recently, we have shown that GMP‐1, a 2‐(methoxymethyl)pyrimido[1,2‐ a ] benzimidazol‐4‐ol protects mitochondrial function in drosophila and mice models of AD, improved memory and behavior indicating neuroprotective effect of GMP‐1 treatment. Here, we have found that GMP‐1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Method Using UV/Vis Spectroscopy we have determined specificity and stoichiometry of metal binding to GMP‐1. To investigate GMP‐1 impact on metal‐dependent enzymatic reactions we have used proteolysis assay with Zn 2+ ‐dependent collagenase and Cu 2+ ‐dependent cytochrome c oxidase assay. Time course thioflavin T fluorescence was used to assess the effect of GMP‐1 and its analogues on amyloid beta fibrillization in the presence of Cu 2+ . The effect of GMP‐1 and its analogues on ROS production and viability of differentiated SH‐SY5Y cells in the presence of amyloid beta and metals was evaluated using DCFDA and TUNEL assay, respectively. Result GMP‐1 specifically binds to copper and zinc, metals that are dysregulated in AD brain. Addition of GMP‐1 does not inhibit metal‐dependent enzymatic reactions. Binding of Zn 2+ and Cu 2+ by the GMP‐1 is weaker than the 8‐hydroxyquinoline scaffold compound clioquinol (CQ) previously tested in AD clinical trials. However, GMP‐1 affects Cu 2+ ‐dependent Ab fibrillization as well as oxidative damage and viability of SH‐SY5Y cells upon addition of Cu 2+ and Ab. Conclusion Our data provide new insight on GMP‐1 as Zn 2+ and Cu 2+ specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models.