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

Nat Med. 2001 Mar;7(3):338-43. doi: 10.1038/85487.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Brain / pathology*
  • Caspase 3
  • Caspases / metabolism*
  • Cell Death / physiology
  • Clusterin
  • Fluorescent Antibody Technique
  • Glycoproteins / genetics
  • Glycoproteins / physiology*
  • Hypoxia-Ischemia, Brain / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Immunoelectron
  • Molecular Chaperones / genetics
  • Molecular Chaperones / physiology*


  • Clu protein, mouse
  • Clusterin
  • Glycoproteins
  • Molecular Chaperones
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases