The role of energy metabolism in the pathogenesis of Alzheimer's disease

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Clough, Richard R.
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In Alzheimer's disease, neuronal degeneration due to apoptosis has been linked to overexpression and aberrant amyloidogenic processing of the amyloid precursor protein (APP), as well as to bioenergetic defects characterized by deficits in the electron transport chain's cytochrome c oxidase (COX) which leads to the genera ion of radical oxygen species. Inhibition of oxidative energy metabolism increased the amyloidogenic processing of APP, which led to neurotoxicity. Overexpression of APP in cultured normal human muscle fibres caused a specific decrease in COX activity, followed by ultrastructural abnormalities of mitochondria. We have demonstrated, using the yeast two-hybrid system, that APP interacts with COX subunit 1 (COX I), and that this interaction involves the extracellular domain of APP. We demonstrated that APP caused specific deficits in COX activity, induced the production of radical oxygen species and lipid peroxidation, and enhanced neuronal apoptosis. However, anti-oxidant enzyme activity was variable, and probably represented a compensatory reaction to elevated oxygen radicals. To directly interact with COY, APP must be targeted to, and localized in, mitochondria. This possibility was tested with an ' in vitro' mitochondrial import assay which showed that APP is transported to mitochondria in an energy-dependent manner. Furthermore, dual fluorescence microscopy with chimeric APP-green fluorescent protein, and immunoelectron microscopy, demonstrated the presence of endogenous APP and B-amyloid peptide (the neurotoxic cleavage product of APP) in mitochondria of postmortem human brain tissue, with increased levels of B-amyloid peptide in AD brains compared to non-AD brains. (Abstract shortened by UMI.)