β‐Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria

Abstract

Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been demonstrated in Alzheimer's disease, and after the expression of the amyloid precursor protein (APP) in cultured cells, suggesting that mitochondria might be involved in L L-amyloid toxicity. Recent evidence suggests that the proteolysis of APP to generate L L-amyloid is at least in part intracellular, preceding the deposition of extracellular fibrils. We have therefore investigated the effect of incubation of isolated rat brain mitochondria with the L L-amyloid fragment 25^35 (100 W WM) on the activities of the mitochondrial respiratory chain complexes I, II^III, IV (cytochrome c oxidase) and citrate synthase. The peptide caused 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 measured. We conclude that inhibition of mitochondrial complex IV might be a contributing factor to the pathogenesis of Alzheimer's disease.z 1999 Federation of European Biochemical Societies.

Aβ(31–35) and Aβ(25–35) fragments of amyloid beta‐protein induce cellular death through apoptotic signals: Role of the redox state of methionine‐35

“…Therefore, this peptide exhibits significant levels of molecular aggregation, retaining the toxicity of the full-length peptide, although it is lacking of metal binding sites. In line with this finding, it has been proposed that Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide represents the biologically active region of Ab [6,7]. However, although the deposition of Ab in the central nervous system is a hallmark of AD and a possible cause of neurodegeneration [1,8,9], several reports have suggested that some non-aggregated amyloid molecules and its peptide fragments, may intercalate into the plasma membrane and directly alter membrane activities [10,11].…”

“…Previous papers have reported that programmed cell death pathways may be involved in the mechanisms responsible for AD [14,15]. On the basis of these findings, it seems particularly interesting to further investigate the mechanism of toxicity induced by the non-aggregated forms of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), trying to evidence the existence of apoptotic events in the toxic mechanism mediated by Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…However, although the deposition of Ab in the central nervous system is a hallmark of AD and a possible cause of neurodegeneration [1,8,9], several reports have suggested that some non-aggregated amyloid molecules and its peptide fragments, may intercalate into the plasma membrane and directly alter membrane activities [10,11]. Recent studies evidenced that at earlier stages of AD, the non-aggregated form of Ab fragments namely Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) mono/oligomer forms are also able to cross the cellular plasmatic membranes inducing intracellular mechanisms of toxicity [12,13]. Previous papers have reported that programmed cell death pathways may be involved in the mechanisms responsible for AD [14,15].…”

“…Abbreviations: Ab, amyloid beta-peptide; AD, AlzheimerÕs disease; DMSO, dimethylsulfoxide; FITC, fluorescein isothiocyanate; MTS, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PTP, mitochondrial permeability transition pore; DW m , mitochondrial transmembrane potential Moreover, in this study a comparison was also performed concerning the apoptotic signals caused by Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide with respect to those showed by the Ab(31-35) fragment. On the other hand, it is known that this Ab derived pentapeptide, i.e.…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Once inside mitochondria, Aβ, either produced by APP processing or by direct import, could induce the RC inhibition. Canevari et al, and Casley et al, showed that nonsynaptic brain mitochondria from rats treated with a truncated form of Aβ displayed a specifically complex IV inhibition, whereas other RC complexes remained unaltered (Canevari et al, 1999;Casley et al, 2002). Moreover, Parks et al, reported Aβ-induced complex IV inhibition in rat liver isolated mitochondria (Parks et al, 2001).…”