Neurobiology of Disease (Jun 2004)
AATF protects neural cells against oxidative damage induced by amyloid β-peptide
Abstract
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 β-peptide (Aβ) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Aβ 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. Aβ induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Aβ toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Aβ-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Aβ-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.
