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Currently, therapeutics that modify Alzheimer’s disease (AD)are not available. Increasing age is the primary risk factor for AD and due to an aging global population the urgent need for effective therapeutics increases every year. This Account presents the development of an AD treatment strategy that incorporates diverse compounds with a common characteristic: the ability to redistribute metal ions within the brain. [ABSTRACT FROM AUTHOR]

Copper (Cu) bis(thiosemicarbazonato) metal complexes [CuII(btsc)s] have unique tumor-imaging and treatment properties and more recently have revealed potent neuroprotective actions in animal and cell models of neurodegeneration. However, despite the continued development of CuII(btsc)s as potential therapeutics or diagnostic agents, little is known of the mechanisms involved in cell uptake, subcellular trafficking, and efflux of this family of compounds. Because of their high lipophilicity, it has been assumed that cellular accumulation is through passive diffusion, although this has not been analyzed in detail. The role of efflux pathways in cell homeostasis of the complexes is also largely unknown. In the present study, we investigated the cellular accumulation of the CuII(btsc) complexes CuII(gtsm) and CuII(atsm) in human neuronal (M17) and glial (U87MG) cell lines under a range of conditions. Collectively, the data strongly suggested that CuII(gtsm) and CuII(atsm) may be taken into these cells by combined passive and facilitated (protein-carrier-mediated) mechanisms. This was supported by strong temperature-dependent changes to the uptake of the complexes and the influence of the cell surface protein on Cu accumulation. We found no evidence to support a role for copper-transporter 1 in accumulation of the compounds. Importantly, our findings also demonstrated that Cu from both CuII(gtsm) and CuII(atsm) was rapidly effluxed from the cells through active mechanisms. Whether this was in the form of released ionic Cu or as an intact metal complex is not known. However, this finding highlighted the difficulty of trying to determine the uptake mechanism of metal complexes when efflux is occurring concomitantly. These findings are the first detailed exploration of the cellular accumulation mechanisms of CuII(btsc)s. The study delineates strategies to investigate the uptake and efflux mechanisms of metal complexes in cells, while highlighting specific difficulties and challenges that need to be considered before drawing definitive conclusions. [ABSTRACT FROM AUTHOR]

Bis(thiosemicarbazonato) metal complexes (M(II)(btsc)) have demonstrated potential neuroprotective activity in cell and animal models of Alzheimer's disease (AD). Metal complexes can activate the epidermal growth factor receptor (EGFR), leading to inhibition of amyloid peptide accumulation in neuronal cells. As glial cells also have an important role in modulating neuronal health and survival in AD, we examined the effect of M(II)(btsc) on activity of EGFR in an astroglial cell line. Our findings reveal potent activation of glial EGFR by glyoxalbis(N(4)-methylthiosemicarbazonato)Cu(II)] (Cu(II)(gtsm)). Activation of EGFR by Cu(II)(gtsm) involved phosphorylation of multiple tyrosine residues and was mediated by a cognate ligand-independent process involving M(II)(btsc) inhibition of protein tyrosine phosphatase (PTP) activity. EGFR activation resulted in release of growth factors and cytokines with potential modulatory effects on neuronal function. These studies provide an important insight into the mechanism of action of a neuroprotective M(II)(btsc) and provide a basis for future studies into this novel approach to AD therapy.