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Clusterin increases post-ischemic damages in organotypic hippocampal slice cultures

Boze, Helène
Aronow, Bruce
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Published in Journal of Neurochemistry. 2008, vol. 106, no. 4, p. 1791-803
Abstract Clusterin or apolipoprotein J is a heterodimeric glycoprotein which is known to be increased during tissue involution in response to hormonal changes or injury and under circumstances leading to apoptosis. Previous studies in wild-type (WT) and clusterin-null (Clu-/-) mice indicated a protective role of clusterin over-expression in astrocytes lasting up to 90 days post-ischemia. However, in in vitro and in vivo models of neonatal hypoxia-ischemia, clusterin exacerbates necrotic cell death. We developed recombinant forms of clusterin and examined their effect on propidium iodide uptake, neuronal and synaptic markers as well as electrophysiological recordings in hippocampal slice cultures from Clu-/- and WT mice subjected to oxygen-glucose deprivation (OGD). WT mice displayed a marked up-regulation of clusterin associated with electrophysiological deficits and dramatic increase of propidium iodide uptake 5 days post-OGD. Immunocytochemical and western blot analyses revealed a substantial decrease of neuronal nuclei and synaptophysin immunoreactivity that predominated in WT mice. These findings contrasted with the relative post-OGD resistance of Clu-/- mice. The addition of biologically active recombinant forms of human clusterin for 24 h post-OGD led to the abolishment of the ischemic tolerance in Clu-/- slices. This deleterious effect of clusterin was reverted by the concomitant administration of the NMDA receptor antagonist, d-2-amino-5-phosphonopentanoate. The present data indicate that in an in vitro model of ischemia characterized by the predominance of NMDA-mediated cell death, clusterin exerts a negative effect on the structural integrity and functionality of hippocampal neurons.
Keywords AnimalsBrain Ischemia/metabolism/pathologyCell Hypoxia/genetics/physiologyClusterin/deficiency/genetics/physiologyGlucose/metabolismHippocampus/metabolism/pathologyMiceMice, Inbred C57BLMice, KnockoutN-Methylaspartate/pharmacologyOrgan Culture TechniquesOxygen Consumption/genetics/physiology
Stable URL http://archive-ouverte.unige.ch/unige:1140
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PMID: 18554319
Research groups Groupe Bouras Constantin (neuropsychiatrie) (1)
Groupe Giannakopoulos Panteleimon (psychiatrie générale) (201)
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