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First published online August 6, 2004
Journal of Experimental Biology 207, 3213-3220 (2004)
Published by The Company of Biologists 2004
doi: 10.1242/jeb.01034

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Review Article

Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury

Rona G. Giffard^1,2,*, Lijun Xu¹, Heng Zhao², Whitney Carrico¹, Yibing Ouyang¹, Yanli Qiao^1,2, Robert Sapolsky³, Gary Steinberg², Bingren Hu⁴ and Midori A. Yenari²

¹ Department of Anesthesia, Stanford University, Stanford, CA 94305, USA
² Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA
³ Department of Biology, Stanford University, Stanford, CA 94305, USA
⁴ Cerebral Vascular Disease Research Center, University of Miami School of Medicine, Miami, Florida 33136, USA

^* Author for correspondence at address 1 (e-mail: rona.giffard{at}stanford.edu)

Accepted 15 April 2004

Chaperones, especially the stress inducible Hsp70, have been studied for their potential to protect the brain from ischemic injury. While they protect from both global and focal ischemia in vivo and cell culture models of ischemia/reperfusion injury in vitro, the mechanism of protection is not well understood. Protein aggregation is part of the etiology of chronic neurodegenerative diseases such as Huntington's and Alzheimer's, and recent data demonstrate protein aggregates in animal models of stroke. We now demonstrate that overexpression of Hsp70 in hippocampal CA1 neurons reduces evidence of protein aggregation under conditions where neuronal survival is increased. We have also demonstrated protection by the cochaperone Hdj-2 in vitro and demonstrated that this is associated with reduced protein aggregation identified by ubiquitin immunostaining. Hdj-2 can prevent protein aggregate formation by itself, but can only facilitate protein folding in conjunction with Hsp70. Pharmacological induction of Hsp70 was found to reduce both apoptotic and necrotic astrocyte death induced by glucose deprivation or oxygen glucose deprivation. Protection from ischemia and ischemia-like injury by chaperones thus involves at least anti-apoptotic, anti-necrotic and anti-protein aggregation mechanisms.

Key words: astrocyte, cell culture, global ischemia, HDJ-2, Hsp70, mouse, rat, CA-1, protein aggregation, apoptosis

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