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.
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.
Aleardi
A M
AM
Scuola Superiore Sant'Anna, Piazza Martiri della libertà 33, Pisa, Italy.
Benard
G
G
Augereau
O
O
Malgat
M
M
Talbot
J C
JC
Mazat
J P
JP
Letellier
T
T
Dachary-Prigent
J
J
Solaini
G C
GC
Rossignol
R
R
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
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