Signal transduction pathway of p66shc through ��-amyloid peptides

Increased oxidative stress is the leading mechanism of Aβ induced cell death. P66Shc the growth factor adaptor protein has been implicated as a major regulator of reactive oxygen species (ROS) production hence apoptotic signalling cascade. Accordingly better understanding of p66Shc signalling pathway through the mediation of Aβ may provide clues as to how to protect brain cells from the toxic effects of Aβ. Aβ leads to progressive cell death in a concentration dependent manner. Aβ phosphorylates p66Shc at S36 residue in a dose dependent and time dependent application of Aβ. Similarly Aβ mediates the activation of MKK6 by mediating phosphorylation at S207 residue at the same concentrations and time points. Ectopic expression of p66ShcS36A and MKK6 (TM) protected cells against Aβ induced death suggesting that p66Shc and MKK6 phosphorylation critically influences the toxicity of C6 cells induced by Aβ. Finally ROS scavengers and knock-down against p66Shc and MKK6 significantly decreased ROS production and cell death.