beta-amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria

Defects in mitochondrial oxidative metabolism, in particular decreased acti vity of cytochrome c oxidase, have been demonstrated in Alzheimer's disease , and after the expression of the amyloid precursor protein (APP) in cultur ed cells, suggesting that mitochondria might be involved in beta-amyloid to xicity. Recent evidence suggests that the proteolysis of APP to generate be ta-amyloid is at least in part intracellular, preceding the deposition of e xtracellular fibrils. We have therefore investigated the effect of incubati on of isolated rat brain mitochondria with the beta-amyloid fragment 25-35 (100 mu M) on the activities of the mitochondrial respiratory chain complex es I, II-Ill, IV (cytochrome c oxidase) and citrate synthase, The peptide c aused a rapid, dose-dependent decrease in the activity of complex IV, while it had no effect on the activities on any of the other enzymes tested. The reverse sequence peptide (35-25) had no effect on any of the activities me asured. We conclude that inhibition of mitochondrial complex IV might be a contributing factor to the pathogenesis of Alzheimer's disease. (C) 1999 Fe deration of European Biochemical Societies.