title: Apurinic/apyrimidinic endonuclease 1 upregulation reduces oxidative DNA damage and protects hippocampal neurons from ischemic injury.
abstract: OBJECTIVE
  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 (PI) 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 PI and ischemic preconditioning. APE1 overexpression inhibited the DNA damage response, as evidenced by lower phospho-histone H2A and p53-upregulated modulator of apoptosis 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 after tGCI, and this effect was 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.
  
  
  METHODS
  This is the first study that thoroughly characterizes structural and functional protection against ischemia after APE1 upregulation by measuring synaptic markers, electrophysiological function, and long-term neurological deficits in vivo. Furthermore, disabling the DNA repair activity of APE1 was found to abrogate its protective impact.
  
  
  CONCLUSIONS
  APE1 upregulation, either endogenously or through transgene overexpression, protects DNA, neuronal structures, synaptic function, and behavioral output from ischemic injury.
authors.affiliation: 1 State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University , Shanghai, China .
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Hassan H
authors.initials: HH
authors.lastname: Sulaiman
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Weng
authors.forename: Guohua
authors.initials: G
authors.lastname: Wang
authors.forename: R Anne
authors.initials: RA
authors.lastname: Stetler
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase