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Originally published online as doi:10.2353/ajpath.2008.070975 on April 10, 2008

Published online before print April 10, 2008
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(American Journal of Pathology. 2008;172:1355-1362.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070975

Regulated Intramembrane Proteolysis of the Low-Density Lipoprotein Receptor-Related Protein Mediates Ischemic Cell Death

Rohini Polavarapu*, Jie An*{dagger}, Chen Zhang* and Manuel Yepes*

From the Department of Neurology and Center for Neurodegenerative Disease,* Emory University School of Medicine, Atlanta, Georgia; and the Institute of Pharmacology,{dagger} Shandong University School of Medicine, Jinan, China

The low-density lipoprotein receptor-related protein (LRP), a member of the low-density lipoprotein receptor gene family, mediates cellular signal transduction pathways. In this study we investigated the role of LRP in cell death. We found that incubation of mouse embryonic fibroblasts in serum-free media induces caspase-3 activation, an effect that is attenuated in LRP-deficient (LRP–/–) mouse embryonic fibroblasts. Since we previously demonstrated that middle cerebral artery occlusion (MCAO) in mice induces shedding of the LRP ectodomain, we investigated here whether cerebral ischemia induces regulated intramembrane proteolysis of LRP and whether this process is related to cell death. We found that MCAO induces an increase in {gamma}-secretase activity in the ischemic hemisphere and that treatment with the {gamma}-secretase inhibitor L-685,458 improves the neurological outcome and results in a 50% decrease in the volume of the ischemic lesion. Furthermore, MCAO caused nuclear translocation of the intracellular domain of LRP in neurons within the area of ischemic penumbra, and this effect was attenuated in mice treated with L-685,458. Finally, inhibition of either LRP or {gamma}-secretase attenuated cerebral ischemia-induced caspase-3 cleavage and apoptotic cell death. In summary, our results indicate that {gamma}-secretase-mediated regulated intramembrane proteolysis of LRP results in cell death under ischemic conditions.




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