Casley, Christopher Stuart; (2002) Amyloid beta-peptide induced oxidative stress and mitochondrial respiratory chain damage: A mechanism for cell death in Alzheimer's disease. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Neuritic plaques composed of [beta]-amyloid peptide and compromised cerebral energy metabolism are two characteristic features of Alzheimer's disease. Synthetic [beta]-amyloid peptide is toxic to cultured neurons. The mechanism underlying [beta]-amyloid neurotoxicity is not well defined, but is thought to involve induction of oxidative stress. Recent studies have shown that [beta]-amyloid inhibits mitochondrial enzymes in a neural cell line and in isolated mitochondria. The present study shows that [beta]-amyloid causes mitochondrial dysfunction in primary neuronal cultures, with a much smaller effect on astrocyte cultures. [beta]-Amyloid was found to decrease the number of mitochondria and induced abnormal mitochondrial swelling in neurons. [beta]-Amyloid caused a decrease in cellular ATP of 42% in neurons and 29% in astrocytes in 24 hours. Reduced glutathione levels were also lowered by [beta]-amyloid in both astrocytes (down from 25.2 to 14.9 nmol.mg protein-1) and neurons (down from 5.1 to 2.9 nmol.mg protein-1). [beta]-Amyloid directly inhibited cytochrome oxidase, [beta]-ketoglutarate dehydrogenase and pyruvate dehydrogenase in purified form and in isolated brain mitochondria. The inhibition of these essential mitochondrial enzyme complexes was reflected in an inhibition of integrated mitochondrial respiration by [beta]-amyloid. There is considerable evidence implicating elevated nitric oxide levels in the pathogenesis of Alzheimer's disease. In this study, the deleterious effects of [beta]-amyloid were found to be exacerbated by nitric oxide in cultured astrocytes and neurons and also in isolated mitochondria. Stimulation of endogenous nitric oxide production in astrocytes with cytokines, together with [beta]-amyloid treatment caused a marked increase in cell death and impaired respiration. Treatment of neuronal cultures with the nitric oxide donor DETA-NO exacerbated the toxicity of [beta]-amyloid, while authentic nitric oxide was found to significantly enhance inhibition of respiration caused by [beta]-amyloid in isolated mitochondria. The results of this study suggest that [beta]-amyloid may contribute to the impaired cerebral energy metabolism observed in Alzheimer's disease. In addition, these results suggest that neuronal degeneration due to [beta]-amyloid in Alzheimer's disease may be accelerated by any insult that stimulates excessive NO production such as infection, ischaemic episodes and head trauma.

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