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J. Biol. Chem., Vol. 281, Issue 40, 29468-29478, October 6, 2006

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Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular -Amyloid-induced Inhibition of Complex IV and Limit Apoptosis^*

Vimal Veereshwarayya, Pravir Kumar, Kenneth M. Rosen, Ruben Mestril, and Henry W. Querfurth¹

From the Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135 and Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinois 60153

Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been reported in Alzheimer disease tissue and in cultured cells that overexpress amyloid precursor protein. Mitochondrial dysfunction contributes to neurodegeneration in Alzheimer disease partly through formation of reactive oxygen species and the release of sequestered molecules that initiate programmed cell death pathways. The heat shock proteins (HSP) are cytoprotective against a number of stressors, including accumulations of misfolded proteins and reactive oxygen species. We reported on the property of Hsp70 to protect cultured neurons from cell death caused by intraneuronal -amyloid. Here we demonstrate that Hsp60, Hsp70, and Hsp90 both alone and in combination provide differential protection against intracellular -amyloid stress through the maintenance of mitochondrial oxidative phosphorylation and functionality of tricarboxylic acid cycle enzymes. Notably, -amyloid was found to selectively inhibit complex IV activity, an effect selectively neutralized by Hsp60. The combined effect of HSPs was to reduce the free radical burden, preserve ATP generation, decrease cytochrome c release, and prevent caspase-9 activation, all important mediators of -amyloid-induced neuronal dysfunction and death.

Received for publication, March 17, 2006 , and in revised form, June 27, 2006.

^* This work was supported in part by National Institutes of Health Grant NS41373 (to H. W. Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neurology; Caritas St. Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. Tel.: 617-789-2685; Fax: 617-789-5177; E-mail: henry.querfurth{at}tufts.edu.

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