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8-Hydroxyquinoline Copper Complexes in the Treatment of Neurodegenerative Disease



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Alzheimer’s disease (AD) is among the most prevalent and debilitating of over 40 different incurable human diseases associated with misfolding of one or more specific proteins or peptides, including the amyloid beta (Aβ) peptide. Despite the large volume of research that has focused on understanding AD mechanisms and identifying possible treatments, the field remains divided on what causes the disease, and therefore, what aspect(s) of disease pathology might be targeted to cure AD. One avenue of research hypothesizes that dyshomeostasis of brain metals such as copper, zinc, and iron is a key step in disease progression. To this end, metal chelation has been explored as a possible AD treatment. Promising results with 8-hydroxyquinoline (8HQ) based metal chelators, in both animals and humans, showed improvements in cognition and memory. Although these chelators have been postulated to restore brain metal ion homeostasis, their mechanism of action remains largely unknown. To better determine the mechanism(s) of action of 8HQ chelators, we investigated the solution structure of several 8HQ Cu(II) complexes using synchrotron X-ray absorption spectroscopy (XAS), along with the Cu(II)-binding site in the Aβ peptide, the major component of plaques in AD brains. We investigated metal ion distributions in single cells treated with 8HQs using synchrotron X-ray fluorescence imaging (XFI). We also developed a multimodal imaging technique to map the metal ion distribution (using XFI) and amyloid plaque distribution and composition in mammalian brain tissue using Fourier transform infrared (FTIR) mapping and Raman microscopy. Results from synchrotron techniques, and other more conventional techniques, suggest that the most promising 8HQ-based anti-AD drug, PBT2, binds Cu(II) differently than other 8HQs. These differences in Cu(II) binding appear to allow for different interactions with the Aβ peptide and to cause differential effects on single cells in culture. Our results from studies mapping AD mouse model brain sections show that areas of high aggregated protein (i.e. amyloid plaques), coincide with areas of high iron, copper, and zinc. Results from the multimodal imaging studies set the stage for future investigations into the metal ion redistribution and amyloid plaque degradation that has been proposed to occur following 8HQ treatment. Taken together, these results suggest that the Cu(II) coordination complexes formed with 8HQs in solution are likely to significantly impact their biological action.



Alzheimer's disease, metal ion homeostasis, copper, copper coordination, chelation, 8-hydroxyquinolines, PBT2, X-ray absorption spectroscopy, X-ray fluorescence imaging, synchrotron



Doctor of Philosophy (Ph.D.)






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