Neurotoxic A beta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro

Beta amyloid (A beta) peptides accumulate in Alzheimer's disease and are ne urotoxic possibly through the production of oxygen free radicals. Using bra in microdialysis we characterized the ability of A beta to increase oxygen radical production in vivo. The 1-40 A beta fragment increased 2,3-dehydrox ybenzoic acid efflux more than the 1-28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effe cts of Ap peptides on mitochondrial function in vitro, Induction of the mit ochondrial permeability transition in isolated rat liver mitochondria by A beta (25-35) and A beta (35-25) exhibited dose dependency and required calc ium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the ons et of mitochondrial permeability transition. Electron microscopy confirmed the presence of A beta aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability tra nsition. Cytochrome c oxidase (COX) activity was selectively inhibited by A beta (25-35) but not by A beta (35-25), Neurotoxic A beta peptide can incr ease oxidative stress in vivo through mechanisms involving NMDA receptors a nd nitric oxide sythase. Increased intracellular A beta levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the fe ed-forward hypothesis of A beta neurotoxicity.