| Accumulation of amyloid-beta (Abeta) into senile plaques as well as oxidative stress are considered important contributors that promote neuronal cell loss and subsequent cognitive dysfunction in patients affected with Alzheimer's disease (AD). Abeta is thought to induce neuronal cell death in part through the generation of reactive oxygen species (ROS) and subsequent activation of mitogen-activated protein kinase (MAPK) pathways. Protein phosphatase 5 (PP5) is a ubiquitously expressed serine/threonine phosphatase which has been implicated in several cell stress response pathways and shown to inactivate MAPK pathways through key dephosphorylation events. Therefore, I examined whether PP5 protects dissociated embryonic rat cortical neurons in vitro from cell death evoked by aggregated Abeta or by the direct application of a ROS, H2O2. As predicted, neurons in which PP5 expression was decreased by siRNA treatment were more susceptible to Abeta toxicity, as well as cell death induced by oxidative stress. In contrast, over-expression of PP5, but not the inactive mutant, PP5(H304Q), prevented activation of MAPK pathways and neurotoxicity induced by Abeta. PP5 also prevented cell death caused by direct treatment with H2O 2, but did not prevent Abeta-induced production of ROS. Thus, the neuroprotective effect of PP5 requires its phosphatase activity and lies downstream of Abeta-induced generation of ROS. PP5 over-expression did not block cell death induced by staurosporine, a potent kinase inhibitor known to induce apoptosis, indicating that neuroprotection by PP5 over-expression is not a universal response to all treatments inducing neurotoxicity. Because non-aggregated, soluble oligomeric forms of Abeta have also been implicated in the pathogenesis of AD, I also examined whether PP5 prevented neurotoxicity induced by Abeta oligomers. Indeed, PP5 over-expression, but not PP5(H304Q), blocked cell death induced by oligomeric Abeta. In summary, our data indicate that PP5 plays a pivotal neuroprotective role against cell death induced by Abeta and oxidative stress. Consequently, PP5 might be an effective therapeutic target in AD and other neurodegenerative disorders in which oxidative stress is implicated. These findings may also provide clues to better understand the roles performed by PP5 in diseased or aging brain. |
