APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury

Significance AP endonuclease-1 (APE1)/redox effector factor-1 (Ref-1) is an essential DNA repair enzyme that has been difficult to study mechanistically because of embryonic lethality in conventional knockout animals. Thus, we generated a conditional APE1 knockout model to examine the protective role of endogenous APE1 in experimental stroke. Induced APE1 knockout in adulthood greatly exacerbated neuron and oligodendrocyte loss after mild ischemic stroke and prevented the intrinsic, long-term recovery of sensorimotor function and spatial learning and memory. APE1 knockout also aggravated ischemia-induced destruction of myelin and impairment of axon conduction in white matter. We conclude that APE1 dictates fundamental life and death decisions in both gray and white matter and plays an indispensable role in intrinsic recovery after mild ischemic 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.