Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia |
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Authors: | Han B H DeMattos R B Dugan L L Kim-Han J S Brendza R P Fryer J D Kierson M Cirrito J Quick K Harmony J A Aronow B J Holtzman D M |
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Institution: | Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, USA. |
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Abstract: | Clusterin, 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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