Journal
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES
Volume 37, Issue 4, Pages 207-225Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10863-005-6631-3
Keywords
Alzheimer's disease; amyloid-beta peptide; threshold effect; oxidative phosphorylation; membrane fluidity; cytochrome c release
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Intracellular amyloid beta-peptide (A beta) accumulation is considered to be a key pathogenic factor in sporadic Alzheimer's disease (AD), but the mechanisms by which it triggers neuronal dysfunction remain unclear. We hypothesized that gradual mitochondrial dysfunction could play a central role in both initiation and progression of sporadic AD. Thus, we analyzed changes in mitochondrial structure and function following direct exposure to increasing concentrations of A beta(1-42) and A beta(25-35) in order to look more closely at the relationships between mitochondrial membrane viscosity, ATP synthesis, ROS production, and cytochrome c release. Our results show the accumulation of monomeric A beta within rat brain and muscle mitochondria. Subsequently, we observed four different and additive modes of action of A beta, which were concentration dependent: (i) an increase in mitochondrial membrane viscosity with a concomitant decrease in ATP/O, (ii) respiratory chain complexes inhibition, (iii) a potentialization of ROS production, and (iv) cytochrome c release.
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