Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities.
Disrupted energy metabolism, in particular reduced activity of cytochrome oxidase (EC 1.9.3.1), alpha-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. beta-Amyloid is strongly implicated in Alzheimer's pathology and can be formed intracellularly in neurones. We have investigated the possibility that beta-amyloid itself disrupts mitochondrial function. Isolated rat brain mitochondria have been incubated with the beta-amyloid alone or together with nitric oxide, which is known to be elevated in Alzheimer's brain. Mitochondrial respiration, electron transport chain complex activities, alpha-ketoglutarate dehydrogenase activity and pyruvate dehydrogenase activity have been measured. Beta-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, alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase activities were inhibited by beta-amyloid. The K(m) of cytochrome oxidase for reduced cytochrome c was raised by beta-amyloid. We conclude that beta-amyloid can directly disrupt mitochondrial function, inhibits key enzymes and may contribute to the deficiency of energy metabolism seen in Alzheimer's disease.
Casley
C S
CS
Department of Neurochemistry, Institute of Neurology, London, UK.
Canevari
L
L
Land
J M
JM
Clark
J B
JB
Sharpe
M A
MA
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D004338:Drug Combinations; D004579:Electron Transport / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D004338:Drug Combinations; D004798:Enzymes; D009569:Nitric Oxide