β-Amyloid inhibits integrated mitochondrial respiration
and key enzyme activities

Authors


Address correspondence and reprint requests to M. A. Sharpe, Department of Neurology, Institute of Neurology, University College London Queen Square, London WC1N 3BG, UK. E-mail: m.sharpe@ion.ucl.ac.uk

Abstract

Disrupted energy metabolism, in particular reduced activity of cytochrome oxidase (EC 1.9.3.1), α-ketoglutarate dehydrogenase (EC 1.2.4.2) and pyruvate dehydrogenase (EC 1.2.4.1) have been reported in post-mortem Alzheimer's disease brain. β-Amyloid is strongly implicated in Alzheimer's pathology and can be formed intracellularly in neurones. We have investigated the possibility that β-amyloid itself disrupts mitochondrial function. Isolated rat brain mitochondria have been incubated with the β-amyloid alone or together with nitric oxide, which is known to be elevated in Alzheimer's brain. Mitochondrial respiration, electron transport chain complex activities, α-ketoglutarate dehydrogenase activity and pyruvate dehydrogenase activity have been measured. β-Amyloid caused a significant reduction in state 3 and state 4 mitochondrial respiration that was further diminished by the addition of nitric oxide. Cytochrome oxidase, α-ketoglutarate dehydrogenase and pyruvate dehydrogenase activities were inhibited by β-amyloid. The Km of cytochrome oxidase for reduced cytochrome c was raised by β-amyloid. We conclude that β-amyloid can directly disrupt mitochondrial function, inhibits key enzymes and may contribute to the deficiency of energy metabolism seen in Alzheimer's disease.

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