Clusterin, also known as apolipoprotein J, is a ubiquitously expressed mole
cule thought to influence a variety of processes including cell death. In t
he brain, it accumulates in dying neurons following seizures and hypoxic-is
chemic (H-I) Injury. Despite this, in vivo evidence that clusterin directly
influences cell death is lacking. Following neonatal H-I brain injury in m
ice (a model of cerebral palsy), there was evidence of apoptotic changes (n
euronal caspase-3 activation), as well as accumulation of clusterin in dyin
g neurons. Clusterin-deficient mice had 50% less brain injury following neo
natal H-I. Surprisingly, the absence of clusterin had no effect on caspase-
3 activation, and clusterin accumulation and caspase-3 activation did not c
olocalize to the same cells. Studies with cultured cortical neurons demonst
rated that exogenous purified astrocyte-secreted clusterin exacerbated oxyg
en/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.