The omega‐3 fatty acid, DHA, decreases neuronal cell death in association with altered zinc transport

Abstract

Edited by Jesus AvilaKeywords: DHA Omega-3 fatty acid Zinc ZnT3 M17 human neuronal cell Apoptosis a b s t r a c t Docosahexaenoic acid (DHA) is the major polyunsaturated fatty acid in neuronal cell membranes. We hypothesize that DHA induces a decrease in neuronal cell death through reduced ZnT3 expression and zinc uptake. Exposure of M17 cells to DHA-deficient medium increased the levels of active caspase-3, relative to levels in DHA-replete cells, confirming the adverse effects of DHA deficiency in promoting neuronal cell death. In DHA-treated M17 cells, zinc uptake was 65% less and ZnT3 mRNA and protein levels were reduced in comparison with DHA-depleted cells. We propose that the neuroprotective function of DHA is exerted through a reduction in cellular zinc levels that in turn inhibits apoptosis.

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

“…We observed that zinc does in fact get into cells as shown by our 65 Zn studies [20]. The effect of 5 µM of zinc concentration on cell viability was also tested to confirm the occurrence of apoptosis.…”

Effect of Zinc and DHA on Expression Levels and Post-Translational Modifications of Histones H3 and H4 in Human Neuronal Cells

“…ZnT and Zip proteins appear to have opposite roles in cellular zinc homeostasis, where ZnT transporters reduce intracellular cytoplasmic zinc by promoting zinc efflux from cells or into intracellular vesicles, while Zip transporters increase intracellular cytoplasmic zinc by promoting extracellular and, perhaps, vesicular zinc transport into cytoplasm (Murakami and Hirano 2008). In M17 cells, we detected the expression of these two zinc transporter families, including Zip1, Zip2, Zip3, Zip4, Znt1, ZnT2, ZnT3, ZnT4, ZnT5, ZnT6 and ZnT7 (Suphioglu, De Mel et al 2010a). ZnT3 has been the focus of our studies, as it is associated with brain zinc accumulation, as well as Alzheimer's disease, the condition where the expression was found to be up-regulated (Zhang, Wang et al 2008).…”

“…We therefore used this fundamental idea to investigate the molecular mechanisms underlying the zinc and DHA interaction. With the use of human neuroblastoma cell line M17, we have shown that DHA reduces cellular zinc uptake, possibly mediated by the zinc transporter ZnT3 followed by a significant reduction in pro-apoptotic marker, caspase-3 (Suphioglu, De Mel et al 2010a). This indicates the effect of DHA deficiency in the progression of neurodegenerative disease, which is partly mediated by altered zinc fluxes.…”

“…We propose that the alteration of zinc metabolism may play a significant role in cellular apoptosis, which is a key feature in the pathology of neurodegenerative disorders such as Alzheimer's disease (Mattson and Duan 1999). Using western blot analysis of human neuroblastoma M17 cell line, we observed a link between DHA treatment and inhibition of apoptosis, where more than 66% reduction in active caspase-3 protein levels was detected in cells treated with 20µg/ml DHA, compared with the untreated control (Suphioglu, De Mel et al 2010a). The suppression of activated caspase-3 might be mediated by phosphatidylinositol 3-kinasedependent pathway resulting in the phosphorylation of Akt and DHA may act through this pathway.…”

“…There is an association between DHA levels in the brain and zinc homeostasis, which is particularly interesting as both are involved in neuroprotection. A reduction of DHA levels in the brain causes over expression of ZnT3, a transmembrane proteins that is associated with sequestration of cytoplasmic Zn 2+ into synaptic vesicles (Jayasooriya, Ackland et al 2005), resulting in zinc toxicity and neuronal cell death in cultured neuronal cells (Suphioglu, De Mel et al 2010a;Naganska and Matyja 2006). Mice that lacked a zinctransporting gene ZnT3 were shown to develop fewer and smaller plaques than Alzheimer's-prone mice with the gene (Lee, Cole et al 2002), suggesting that altered zinc homeostasis may contribute to the plaque formation in AD.…”