The genotoxic, extracellular accumulation of
amyloid β (Aβ)
protein and subsequent neuronal cell death are associated with
Alzheimer's disease (AD). APE1/Ref-1, the predominant apurinic/apyrimidinic (
AP) endonuclease and essential in eukaryotic cells, plays a central role in the base excision repair (BER) pathway for repairing oxidized and alkylated bases and single-strand breaks (SSBs) in
DNA. APE1/Ref-1 is also involved in the redox activation of several
trans-acting factors (TFs) in various cell types, but little is known about its role in neuronal functions. There is emerging evidence for APE1/Ref-1's role in neuronal cells vulnerable in AD and other
neurodegenerative disorders, as reflected in its nuclear accumulation in AD brains. An increase in APE1/Ref-1 has been shown to enhance neuronal survival after oxidative stress. To address whether APE1/Ref-1 level or its association with other
proteins is responsible for this protective effect, we used 2-D proteomic analyses and identified cytoskeleton elements (i.e.,
tropomodulin 3,
tropomyosin alpha-3 chain),
enzymes involved in energy metabolism (i.e.,
pyruvate kinase M2, N-acetyl
transferase,
sulfotransferase 1c),
proteins involved in stress response (i.e.,
leucine-rich and death domain, anti-NGF30), and heterogeneous nuclear ribonucleoprotien-H (
hnRNP-H) as being associated with APE1/Ref-1 in Aβ(25-35)-treated rat
pheochromocytoma PC12 and human
neuroblastoma SH-SY5Y cell lines, two common neuronal precursor lines used in Aβ neurotoxicity studies. Because the levels of some of these
proteins are affected in the brains of AD patients, our study suggests a neuroprotective role for APE1/Ref-1 via its association with those
proteins and modulating their cellular functions during Aβ-mediated neurotoxicity.