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

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.