Published online before print November 6, 2008

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(American Journal of Pathology. 2008;173:1795-1805.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080168

Causal Role of Apoptosis-Inducing Factor for Neuronal Cell Death Following Traumatic Brain Injury

Jennifer E. Slemmer^*, Changlian Zhu, Stefan Landshamer, Raimund Trabold^¶, Julia Grohm^||, Ardavan Ardeshiri^¶, Ernst Wagner, Marva I. Sweeney^*, Klas Blomgren^||, Carsten Culmsee^**, John T. Weber and Nikolaus Plesnila^¶

From the Department of Biology,^* University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada; Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands; Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden; Pharmaceutical Biology-Biotechnology, Department of Pharmacy, University of Munich, Germany; Department of Neurosurgery & Institute for Surgical Research,^¶ University of Munich Medical Center-Großhadern, Germany; Department of Pediatric Oncology,|| The Queen Silvia Children’s Hospital, University of Gothenburg, Sweden; Institute for Pharmacology and Toxicology,^** Philipps University Marburg, Germany; School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada; Department of Physiology and Neurodegeneration, Royal College of Surgeons in Ireland, Dublin Ireland

Traumatic brain injury (TBI) consists of two phases: an immediate phase in which damage is caused as a direct result of the mechanical impact; and a late phase of altered biochemical events that results in delayed tissue damage and is therefore amenable to therapeutic treatment. Because the molecular mechanisms of delayed post-traumatic neuronal cell death are still poorly understood, we investigated whether apoptosis-inducing factor (AIF), a pro-apoptotic mitochondrial molecule and the key factor in the caspase-independent, cell death signaling pathway, plays a causal role in neuronal death following TBI. Using an in vitro model of neuronal stretch injury, we demonstrated that AIF translocated from mitochondria to the nucleus of neurons displaying axonal disruption, chromatin condensation, and nuclear pyknosis in a caspase-independent manner, whereas astrocytes remained unaffected. Similar findings were observed following experimental TBI in mice, where AIF translocation to the nucleus coincided with delayed neuronal cell death in both cortical and hippocampal neurons. Down-regulation of AIF in vitro by siRNA significantly reduced stretch-induced neuronal cell death by 67%, a finding corroborated in vivo using AIF-deficient harlequin mutant mice, where secondary contusion expansion was significantly reduced by 44%. Hence, our current findings demonstrate that caspase-independent, AIF-mediated signaling pathways significantly contribute to post-traumatic neuronal cell death and may therefore represent novel therapeutic targets for the treatment of TBI.