AATF protects neural cells against oxidative damage induced by amyloid beta-peptide.
Extensive loss of neurons and synapses in vulnerable regions of the brain is one of the most important pathological features of Alzheimer's disease (AD). Increased oxidative stress has been shown to contribute to the neurodegenerative process in AD. Aggregation of amyloid beta-peptide (Abeta) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Abeta has been shown to induce oxidative stress and apoptosis in many in vivo and in vitro models of AD. We now report that AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). AATF may therefore represent a potential candidate for therapeutic intervention of neurodegeneration in both sporadic and familial forms of AD.
Xie
Jun
J
Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Guo
Qing
Q
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
C417216:Aatf protein, mouse; D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; C075222:amyloid beta-protein (1-42)