Redox factor-1 (Ref-1), also known as HAP1, APE or APEX, is a multifunctional protein that regulates gene transcription as well as the response to oxidative stress. By interacting with transcription factors such as AP-1, NF-kappaB and p53, and directly participating in the cleavage of apurininic/apyrimidinic DNA lesions, Ref-1 plays crucial roles in both cell death signaling pathways and DNA repair, respectively. Oxidative stress induced by aggregated beta-amyloid (Aβ) peptide, altered DNA repair and transcriptional activation of cell death pathways have been implicated in the pathophysiology of Alzheimer’s disease (AD). Here we show that varying concentrations of Aβ1-42 differentially regulate Ref-1 expression, Ref-1 function and neuronal survival in vitro. Aβ (5.0 μM) caused a relatively rapid decrease in Ref-1 expression and activity associated with extensive DNA damage and neuronal degeneration. In contrast, Ref-1 induction occurred in cells exposed to Aβ (1.0 μM) without significant neuronal cell death. Aβ-induced attenuation of Ref-1 expression and endonuclease activity, and neuronal cell death were prevented by the anti-oxidant, catalase. Similar differential effects on Ref-1 expression and cell viability were observed in N2A neuroblastoma cells treated with either high or low dose hydrogen peroxide. These findings demonstrate the differential regulation of Ref-1 expression by varying degrees of oxidative stress. Parallels between the Ref-1 response to Aβ and H2O2 suggest similarities between DNA repair pathways activated by different inducers of oxidative stress. In AD brain, colocalization of Ref-1 and Aβ the absence of significant DNA damage are consistent with the cell culture results and suggests that Ref-1 may play a more neuroprotective role under these conditions. Modulation of Ref-1 expression and activity by local variations in Aβ concentration may be an important determinant of neuronal vulnerability to oxidative stress in AD.
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