Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia.
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.
Han
B H
BH
Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, USA.
DeMattos
R B
RB
Dugan
L L
LL
Kim-Han
J S
JS
Brendza
R P
RP
Fryer
J D
JD
Kierson
M
M
Cirrito
J
J
Quick
K
K
Harmony
J A
JA
Aronow
B J
BJ
Holtzman
D M
DM
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D051152:Clusterin; D005455:Fluorescent Antibody Technique; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*
C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases