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• W2033624360 abstract "Altered biometal homeostasis is a feature of the Alzheimer's disease (AD) brain and restoring normal biometal metabolism may therefore offer a unique therapeutic opportunity. Supporting this, we have previously shown that a bis(thio)semi-carbazonato copper complex (CuBTSC) capable of increasing intracellular Cu bio-availability inhibits the accumulation of trimeric Aβ and phosphorylated tau in the brains of AD model mice and restores their cognitive function. CuBTSCs have also produced positive effects in other neurodegenerative disease models. With the current project we sought to determine how the metal complexes are taken up and trafficked to provide a greater understanding of their metabolism and potential use in AD therapy. U87MG glial cells and M17 human neuroblastoma cells were treated with CuGTSM and CuATSM as well as a fluorescent pyrene-derivatized version of CuATSM (termed Y31). Cells were analyzed using confocal microspcopy in conjunction with organelle trackers. Cells were also examined for metal uptake by inductively coupled plasma-mass spectrometry (ICP-MS). Our confocal microscopy data using fluorescent Y31 revealed the presence of large, distinct vesicles in M17 cells, that were morphologically consistent with autophagic vacuoles (AVs). Identity of the AVs was supported by colocalisation of lysosomal markers. The formation of AVs in cells treated with the non-fluorescent CuATSM was demonstrated using the AV marker monodansyl cadaverine (MDC). AV formation following treatment with CuATSM was inhibited by co-treating with 3-methyl adenine. While CuATSM-treated M17 cells were positive for MDC stained AVs, CuGTSM-treated M17 cells were not, suggesting metal complex-specific metabolism. CuATSM retains its Cu intracellularly while CuGTSM releases the Cu. AVs were not observed in the U87MG glial cell line. Preliminary ICP-MS data has confirmed that the uptake mechanisms of CuGTSM and CuATSM are distinct. Furthermore, trafficking of CuATSM and CuGTSM is cell-type specific, indicating that multiple, complex mechanisms are involved in the metabolism of metal complexes. This study demonstrates that cell uptake and metabolism of potentially therapeutic metal complexes is specific to the backbone structure of the complex and the cell-type examined. Whether autophagic processes are involved in the therapeutic activity of some CuBTSCs remains to be determined." @default.
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• W2033624360 date "2009-07-01" @default.
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• W2033624360 title "P3-242: The role of autophagy in potentially therapeutic copper complexes" @default.
• W2033624360 doi "https://doi.org/10.1016/j.jalz.2009.04.1015" @default.
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