Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia.
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 (approximately 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.
Culmsee
Carsten
C
Department of Pharmacy, Walter Brendel Center for Experimental Medicine, University of Munich, D-81377 Munich, Germany.
Zhu
Changlian
C
Landshamer
Stefan
S
Becattini
Barbara
B
Wagner
Ernst
E
Pellecchia
Maurizio
M
Pellechia
Maurizio
M
Blomgren
Klas
K
Plesnila
Nikolaus
N
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000502:physiology*; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D051381:Rats
D051033:Apoptosis Inducing Factor; D051023:BH3 Interacting Domain Death Agonist Protein; D011065:Poly(ADP-ribose) Polymerases; D005947:Glucose; D010100:Oxygen