APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury.
A major hallmark of oxidative DNA damage after stroke is the induction of apurinic/apyrimidinic (AP) sites and strand breaks. To mitigate cell loss after oxidative DNA damage, ischemic cells rapidly engage the base excision-repair proteins, such as the AP site-repairing enzyme AP endonuclease-1 (APE1), also named redox effector factor-1 (Ref-1). Although forced overexpression of APE1 is known to protect against oxidative stress-induced neurodegeneration, there is no concrete evidence demonstrating a role for endogenous APE1 in the long-term recovery of gray and white matter following ischemic injury. To address this gap, we generated, to our knowledge, the first APE1 conditional knockout (cKO) mouse line under control of tamoxifen-dependent Cre recombinase. Using a well-established model of transient focal cerebral ischemia (tFCI), we show that induced deletion of APE1 dramatically enlarged infarct volume and impaired the recovery of sensorimotor and cognitive deficits. APE1 cKO markedly increased postischemic neuronal and oligodendrocyte degeneration, demonstrating that endogenous APE1 preserves both gray and white matter after tFCI. Because white matter repair is instrumental in behavioral recovery after stroke, we also examined the impact of APE1 cKO on demyelination and axonal conduction and discovered that APE1 cKO aggravated myelin loss and impaired neuronal communication following tFCI. Furthermore, APE1 cKO increased AP sites and activated the prodeath signaling proteins, PUMA and PARP1, after tFCI in topographically distinct manners. Our findings provide evidence that endogenous APE1 protects against ischemic infarction in both gray and white matter and facilitates the functional recovery of the central nervous system after mild stroke injury.
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
R Anne
RA
Stetler
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213;
Yanqin
Y
Gao
Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282;
Rehana K
RK
Leak
Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Zhongfang
Z
Weng
Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Yejie
0000-0001-7502-9201
Y
Shi
Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Lili
L
Zhang
Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213;
Hongjian
H
Pu
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Feng
F
Zhang
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Xiaoming
X
Hu
Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Sulaiman
S
Hassan
Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261;
Carolyn
C
Ferguson
Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261;
Gregg E
GE
Homanics
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261;
Guodong
G
Cao
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461 michael.bennett@einstein.yu.edu chenj2@upmc.edu.
Michael V L
MV
Bennett
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China; Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261; michael.bennett@einstein.yu.edu chenj2@upmc.edu.
Jun
J
Chen
D000818:Animals; D001522:Behavior, Animal; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000502:physiology*; D066128:Gray Matter / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020521:Stroke / Q000503:physiopathology*; D066127:White Matter / Q000503:physiopathology*
C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
base excision repair; ischemia; neurodegeneration; oxidative DNA damage; white matter injury