Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia

Byung Hee Han, Ronald B. DeMattos, Laura L. Dugan, Jeong Sook Kim-Han, Robert P. Brendza, John D. Fryer, Malca Kierson, John Cirrito, Kevin Quick, Judith A.K. Harmony, Bruce J. Aronow, David M. Holtzman

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168 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)338-343
Number of pages6
JournalNature Medicine
Volume7
Issue number3
DOIs
StatePublished - Mar 29 2001

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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. K., Aronow, B. J., & Holtzman, D. M. (2001). Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia. Nature Medicine, 7(3), 338-343. https://doi.org/10.1038/85487