Affiliations: [a] Department of Neurobiology, Care sciences and Societ, Centre for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden
| [b] Memory Clinic, Theme Aging, Karolinska University Hospital, Huddinge, Sweden
Correspondence:
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Correspondence to: Prof. Bengt Winblad, Karolinska Institutet, Centre for Alzheimer Research, Department of Neuroscience Care and Society, Division of Neurogeriatrics, J9 : 20, Bioclinicum, Solna S-17164, Sweden. E-mail: bengt.winblad@ki.se.
Abstract: Alzheimer’s disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-β (Aβ) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. 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, and 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. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aβ fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aβ. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models.
Keywords: Alzheimer’s disease, metal chelation, multi-target-directed ligands, treatment strategies
