APE1 upregulation reduces oxidative DNA damage and protects hippocampal neurons from ischemic injury


Dr. Rehana K. Leak, Dr. Peiying Li, Dr. Feng Zhang, Mr. Hassan H. Sulaiman, Dr. Zhongfang Weng, Dr. Guohua Wang, Prof. Ruth Anne Stetler, Dr. Yejie Shi, Dr. Guodong Cao, Dr. Yanqin Gao, and Prof. Jun Chen


Aims: Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional enzyme that participates in base-excision repair of oxidative DNA damage and in the redox activation of transcription factors. We tested the hypothesis that APE1 upregulation protects neuronal structure and function against transient global cerebral ischemia (tGCI).
Results: Upregulation of APE1 by low-dose proton irradiation or by transgene overexpression protected hippocampal CA1 neurons against tGCI-induced cell loss and reduced apurinic/apyrimidinic sites and DNA fragmentation. Conversely, APE1 knockdown attenuated the protection afforded by proton irradiation and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A (H2AX) and p53-upregulated modulator of apoptosis (PUMA) levels. APE1 overexpression also partially rescued dendritic spines and attenuated the decrease in field excitatory postsynaptic potentials in hippocampal CA1. Presynaptic and postsynaptic markers were reduced following tGCI and this effect was also blunted in APE1 transgenics. The Morris water maze test revealed that APE1 protected against learning and memory deficits for at least 27 days post-injury. Animals expressing DNA repair-disabled mutant APE1 (D210A) exhibited more DNA damage than wild-type controls and were not protected against tGCI-induced cell loss. 
Innovation: This is the first study to thoroughly characterize structural and functional protection against ischemia following APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits <i>in vivo</i>. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact.
Conclusion: APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury.