“Mitochondrial dysfunction and oxidative metabolism are principal sources of oxidative stress leading to neurodegeneration, although NAD(P)H oxidase and other sources of free radicals also contribute.
Neurons have high energy demands (ATP consumption) associated with membrane ionic pumps, channel activity, and synaptic transmission, which can lead to increased free radical production. Elevation in free radicals can increase levels of glutathione disulfide (GSSG) which inhibits the thiol-dependent enzyme NADH dehydrogenase, causing a mitochondrial complex I defect. Mitochondrial dysfunction can lead to neuronal degeneration via impaired production of ATP (through disruption of the electron transport chain (ETC)), increased generation of reactive oxygen species (ROS), altered calcium homeostasis and excitotoxicity. Brains of aged animals have significantly higher levels of oxidized proteins and lipids, and reduced protease activities compared to young animals.