Protein phosphatase 5 protects neurons against amyloid-beta toxicity.
Amyloid-beta (Abeta) is thought to promote neuronal cell loss in Alzheimer's disease, 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, we examined whether PP5 protects dissociated embryonic rat cortical neurons in vitro from cell death evoked by Abeta. As predicted, neurons in which PP5 expression was decreased by small-interfering RNA treatment were more susceptible to Abeta toxicity. In contrast, over-expression of PP5, but not the inactive mutant, PP5(H304Q), prevented MAPK phosphorylation and neurotoxicity induced by Abeta. PP5 also prevented cell death caused by direct treatment with H(2)O(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. 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 Alzheimer's disease and other neurodegenerative disorders in which oxidative stress is implicated.
Sanchez-Ortiz
Efrain
E
Department of Biochemistry and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Hahm
Byoung Kwon
BK
Armstrong
David L
DL
Rossie
Sandra
S
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D016229:Amyloid beta-Peptides; D009687:Nuclear Proteins; D016877:Oxidants; D006861:Hydrogen Peroxide; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5
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