title: 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.
abstract: 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.
authors.affiliation: Scuola Superiore Sant'Anna, Piazza Martiri della libertà 33, Pisa, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Aleardi
authors.forename: G
authors.initials: G
authors.lastname: Benard
authors.forename: O
authors.initials: O
authors.lastname: Augereau
authors.forename: M
authors.initials: M
authors.lastname: Malgat
authors.forename: J C
authors.initials: JC
authors.lastname: Talbot
authors.forename: J P
authors.initials: JP
authors.lastname: Mazat
authors.forename: T
authors.initials: T
authors.lastname: Letellier
authors.forename: J
authors.initials: J
authors.lastname: Dachary-Prigent
authors.forename: G C
authors.initials: GC
authors.lastname: Solaini
authors.forename: R
authors.initials: R
authors.lastname: Rossignol
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D045304:Cytochromes c / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014783:Viscosity
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D000255:Adenosine Triphosphate; D045304:Cytochromes c; D011451:Prostaglandin-Endoperoxide Synthases