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The Journal of Neuroscience, November 2, 2005, 25(44):10262-10272; doi:10.1523/JNEUROSCI.2818-05.2005

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Neurobiology of Disease
Apoptosis-Inducing Factor Triggered by Poly(ADP-Ribose) Polymerase and Bid Mediates Neuronal Cell Death after Oxygen-Glucose Deprivation and Focal Cerebral Ischemia

Carsten Culmsee,¹ Changlian Zhu,³ Stefan Landshamer,¹ Barbara Becattini,⁵ Ernst Wagner,¹ Maurizio Pellecchia,⁵ Klas Blomgren,^3,4 and Nikolaus Plesnila²

¹Biotechnology and Pharmaceutical Biology, Department of Pharmacy and ²Laboratory of Experimental Neurosurgery, Walter Brendel Center for Experimental Medicine, University of Munich, D-81377 Munich, Germany, ³Arvid Carlsson Institute of Neuroscience, Sahlgrenska Academy and ⁴Department of Pediatrics, The Queen Silvia Children's Hospital, Göteborg University, SE 405 30 Göteborg, Sweden, and ⁵The Burnham Institute, La Jolla, California 92037

Delayed neuronal cell death occurring hours after reperfusion is a hallmark of ischemic stroke and a primary target for neuroprotective strategies. In the present study, we investigated whether apoptosis-inducing factor (AIF), a caspase-independent proapoptotic protein, is responsible for neuronal cell death after glutamate toxicity and oxygen-glucose deprivation (OGD) in vitro and after experimental stroke in vivo. AIF translocated to the nucleus in which it colocalized with DNA fragmentation and nuclear apoptotic morphology after exposure to glutamate or OGD in cultured neurons or after transient middle cerebral artery occlusion (MCAo) in mice. Small inhibitory RNA-mediated downregulation of AIF reduced glutamate- and OGD-induced neuronal apoptosis by 37 and 60%, respectively (p < 0.01). Moreover, Harlequin mutant mice, which express AIF at low levels (20% of wild-type mice), displayed smaller infarct volumes (-43%; p < 0.03) and showed dramatically reduced cell death in the ischemic penumbra after 45 min of MCAo compared with wild-type littermates. Inhibition of poly(ADP-ribose) polymerase and Bid reduced nuclear AIF translocation. These results provide the first evidence for a causal role of AIF in ischemic neuronal cell death. Therefore, caspase-independent cell death signaling may provide a promising novel target for therapeutic interventions in cerebrovascular diseases.

Key words: cerebral ischemia; stroke; neuronal cell death; apoptosis-inducing factor; poly(ADP-ribose) polymerase; Bid

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Received March 1, 2005; revised September 23, 2005; accepted September 27, 2005.

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