Published online before print January 10, 2008

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(American Journal of Pathology. 2008;172:454-469.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070876

Inhibition of Autophagy Prevents Hippocampal Pyramidal Neuron Death after Hypoxic-Ischemic Injury

Masato Koike^*, Masahiro Shibata^*, Masao Tadakoshi^*, Kunihito Gotoh^*, Masaaki Komatsu, Satoshi Waguri, Nobutaka Kawahara^¶, Keisuke Kuida^||, Shigekazu Nagata^**, Eiki Kominami, Keiji Tanaka and Yasuo Uchiyama^*

From the Department of Cell Biology and Neurosciences,^*Osaka University Graduate School of Medicine, Osaka, Japan; the Department of Biochemistry,Juntendo University School of Medicine, Tokyo, Japan; the Department of Anatomy and Histology,Fukushima Medical University School of Medicine, Fukushima, Japan; the Department of Neurosurgery,^¶Graduate School of Medicine, University of Tokyo, Tokyo, Japan; the Department of Medical Chemistry,^**Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Laboratory of Frontier Science,Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; and Vertex Pharmaceuticals,||Cambridge, Massachusetts

Neonatal hypoxic/ischemic (H/I) brain injury causes neurological impairment, including cognitive and motor dysfunction as well as seizures. However, the molecular mechanisms regulating neuron death after H/I injury are poorly defined and remain controversial. Here we show that Atg7, a gene essential for autophagy induction, is a critical mediator of H/I-induced neuron death. Neonatal mice subjected to H/I injury show dramatically increased autophagosome formation and extensive hippocampal neuron death that is regulated by both caspase-3-dependent and -independent execution. Mice deficient in Atg7 show nearly complete protection from both H/I-induced caspase-3 activation and neuron death indicating that Atg7 is critically positioned upstream of multiple neuronal death executioner pathways. Adult H/I brain injury also produces a significant increase in autophagy, but unlike neonatal H/I, neuron death is almost exclusively caspase-3-independent. These data suggest that autophagy plays an essential role in triggering neuronal death execution after H/I injury and Atg7 represents an attractive therapeutic target for minimizing the neurological deficits associated with H/I brain injury.

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