Gradual alteration of mitochondrial structure and function by beta-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release

• Published in: Journal of bioenergetics and biomembranes Vol. 37; no. 4; pp. 207 - 225
• Main Authors: Aleardi, A M, Benard, G, Augereau, O, Malgat, M, Talbot, J C, Mazat, J P, Letellier, T, Dachary-Prigent, J, Solaini, G C, Rossignol, R
• Format: Journal Article
• Language: English
• Published: United States 01.08.2005
• Subjects: Adenosine Triphosphate - biosynthesis; Alzheimer Disease - metabolism; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Animals; Antioxidants - pharmacology; Brain - drug effects; Brain - enzymology; Brain - metabolism; Brain - ultrastructure; Cytochromes c - metabolism; Cytochromes c - secretion; Intracellular Membranes - drug effects; Intracellular Membranes - enzymology; Intracellular Membranes - metabolism; Male; Membrane Fluidity - drug effects; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - enzymology; Mitochondria, Muscle - metabolism; Oxygen Consumption - drug effects; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Viscosity
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-005-6631-3

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.