Nature Medicine
7, 338 - 343 (2001)
doi:10.1038/85487
Clusterin contributes to caspase-3−independent brain injury following neonatal hypoxia-ischemiaByung Hee Han1, 2, Ronald B. DeMattos1, 2, Laura L. Dugan1, 2, Jeong Sook Kim-Han1, 2, Robert P. Brendza1, 2, John D. Fryer1, 2, Malca Kierson1, 2, John Cirrito1, 2, Kevin Quick1, 2, Judith A. K. Harmony4, Bruce J. Aronow5
& David M. Holtzman1, 2, 31
Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, USA
2
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
3
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA
4
Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
5
Division of Molecular and Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA
Correspondence should be addressed to David M. Holtzman holtzman@neuro.wustl.eduClusterin, also known as apolipoprotein J, is a ubiquitously expressed molecule thought to influence a variety of processes including cell death. In the brain, it accumulates in dying neurons following seizures and hypoxic-ischemic (H-I) injury. Despite this, in vivo evidence that clusterin directly influences cell death is lacking. Following neonatal H-I brain injury in mice (a model of cerebral palsy), there was evidence of apoptotic changes (neuronal caspase-3 activation), as well as accumulation of clusterin in dying neurons. Clusterin-deficient mice had 50% less brain injury following neonatal H-I. Surprisingly, the absence of clusterin had no effect on caspase-3 activation, and clusterin accumulation and caspase-3 activation did not colocalize to the same cells. Studies with cultured cortical neurons demonstrated that exogenous purified astrocyte-secreted clusterin exacerbated oxygen/glucose-deprivation−induced necrotic death. These results indicate that clusterin may be a new therapeutic target to modulate non-caspase-dependent neuronal death following acute brain injury.
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