Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity.
Alzheimer's disease (AD) brain reveals high rates of oxygen consumption and oxidative stress, altered antioxidant defences, increased oxidized polyunsaturated fatty acids, and elevated transition metal ions. Mitochondrial dysfunction in AD is perhaps relevant to these observations, as such may contribute to neurodegenerative cell death through the formation of reactive oxygen species (ROS) and the release of molecules that initiate programmed cell death pathways. In this study, we analyzed the effects of beta-amyloid peptide (Abeta) on human teratocarcinoma (NT2) cells expressing endogenous mitochondrial DNA (mtDNA), mtDNA from AD subjects (AD cybrids), and mtDNA from age-matched control subjects (control cybrids). In addition to finding reduced cytochrome oxidase activity, elevated ROS, and reduced ATP levels in the AD cybrids, when these cell lines were exposed to Abeta 1-40 we observed excessive mitochondrial membrane potential depolarization, increased cytoplasmic cytochrome c, and elevated caspase-3 activity. When exposed to Abeta, events associated with programmed cell death are activated in AD NT2 cybrids to a greater extent than they are in control cybrids or the native NT2 cell line, suggesting a role for mtDNA-derived mitochondrial dysfunction in AD degeneration.
Cardoso
Sandra M
SM
Laboratory of Biochemistry, Faculty of Medicine and Center for Neurosciences and Cell Biology, University Hospital, University of Coimbra, 3005-504 Coimbra, Portugal.
Santana
Isabel
I
Swerdlow
Russell H
RH
Oliveira
Catarina R
CR
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D020169:Caspases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport / Q000187:drug effects / Q000235:genetics; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000637:transplantation; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000633:toxicity*; D010718:Phosphatidylserines / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018243:Teratocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D010446:Peptide Fragments; D010718:Phosphatidylserines; D011506:Proteins; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003576:Electron Transport Complex IV; D020169:Caspases