β-Amyloid inhibits integrated mitochondrial respiration and key enzyme activities

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 K_m 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.