β-Amyloid-evoked Apoptotic Cell Death is Mediated Through MKK6–p66shc Pathway

Abstract

We have previously shown the involvement of p66shc in mediating apoptosis. Here, we demonstrate the novel mechanism of β-Amyloid-induced toxicity in the mammalian cells. β-Amyloid leads to the phosphorylation of p66shc at the serine 36 residue and activates MKK6, by mediating the phosphorylation at serine 207 residue. Treatment of cells with antioxidants blocks β-Amyloid-induced serine phosphorylation of MKK6, reactive oxygen species (ROS) generation, and hence protected cells against β-Amyloid-induced cell death. Our results indicate that serine phosphorylation of p66shc is carried out by active MKK6. MKK6 knock-down resulted in decreased serine 36 phosphorylation of p66shc. Co-immunoprecipitation results demonstrate a direct physical association between p66shc and WT MKK6, but not with its mutants. Increase in β-Amyloid-induced ROS production was observed in the presence of MKK6 and p66shc, when compared to triple mutant of MKK6 (inactive) and S36 mutant of p66shc. ROS scavengers and knock-down against p66shc, and MKK6 significantly decreased the endogenous level of active p66shc, ROS production, and cell death. Finally, we show that the MKK6-p66shc complex mediates β-Amyloid-evoked apoptotic cell death.

The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain

“…Treatment with different familial or sporadic variants of Aβ has been shown to induce apoptosis in multiple brain cell types, including neuronal and glial cells (Bashir et al, 2014; Fossati et al, 2013; Modi et al, 2014). We therefore challenged neuronal SHSY-5Y cells, M059K glioma cells and Normal Human Astrocytes with WT-Aβ42 (10 μM), and the Dutch mutant of Aβ40 (Aβ40-Q22, 50 μM).…”

Effect of human umbilical cord blood derived lineage negative stem cells transplanted in amyloid-β induced cognitive impaired mice

“…Recently, it has been reported that A␤ induced neuronal apoptosis is mediated by increased ROS production [39]. Postmortem study in AD patients also revealed increased Fas expression and Fas-L immunoreactivity on reactive astrocytes in frontal and hippocampus region, especially in tangle-bearing and non-tangle-bearing neurons [40].…”

Delivery of Constitutively Active Mutant MKK6(E) With TAT-OSBP Induces Apoptosis in Human Ovarian Carcinoma HO8910 Cells

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