Differential effects of mitochondrial heat shock protein 60 and related molecular chaperones to prevent intracellular beta-amyloid-induced inhibition of complex IV and limit apoptosis.
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 beta-amyloid. Here we demonstrate that Hsp60, Hsp70, and Hsp90 both alone and in combination provide differential protection against intracellular beta-amyloid stress through the maintenance of mitochondrial oxidative phosphorylation and functionality of tricarboxylic acid cycle enzymes. Notably, beta-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 beta-amyloid-induced neuronal dysfunction and death.
Veereshwarayya
Vimal
V
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Kumar
Pravir
P
Rosen
Kenneth M
KM
Mestril
Ruben
R
Querfurth
Henry W
HW
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*
D016229:Amyloid beta-Peptides; D018834:Chaperonin 60; D003576:Electron Transport Complex IV