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

Nature Medicine volume 7, pages 338–343 (2001)Cite this article

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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Figure 1: Caspase-3 activation and clusterin accumulation following neonatal H-I brain injury in P7 C57Bl6 mice.
Figure 2: Decreased brain injury in Clu−/− mice following neonatal H-I.
Figure 3: Clusterin does not influence caspase-3 activation following H-I.
Figure 4: Clusterin potentiates neuronal death induced by oxygen/glucose deprivation (OGD) in cortical cultures.

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Acknowledgements

We thank M. Parsadanian for technical assistance. This work was supported by NIH grants NS35902, AG11355, and AG05681 to D.M.H.

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Authors and Affiliations

  1. Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, USA

    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 & David M. Holtzman

  2. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

    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 & David M. Holtzman

  3. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA

    David M. Holtzman

  4. Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Judith A. K. Harmony

  5. Division of Molecular and Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA

    Bruce J. Aronow

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Correspondence to David M. Holtzman.

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Han, B., DeMattos, R., Dugan, L. et al. Clusterin contributes to caspase-3–independent brain injury following neonatal hypoxia-ischemia. Nat Med 7, 338–343 (2001). https://doi.org/10.1038/85487

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