Superoxide mediates the cell-death-enhancing action of presenilin-1 mutations.
The mechanism whereby mutations in the presenilin-1 (PS-1) gene on chromosome 14 cause early-onset inherited Alzheimer's disease are unknown. We report that PC6 neural cells (a subclone of PC12 cells) expressing PS-1 mutations (M146V and L286V) exhibit increased superoxide production, nitrotyrosine accumulation, and membrane lipid peroxidation following exposure to amyloid beta-peptide 1-42 (Abeta). Mitochondrial calcium accumulation and membrane depolarization following exposure to Abeta were enhanced in cells expressing mutant PS-1. Overexpression of mitochondrial Mn-SOD greatly reduced superoxide production, nitrotyrosine formation, membrane lipid peroxidation, intramitochondrial calcium accumulation, and membrane depolarization following exposure to Abeta and conferred resistance to the apoptosis-enhancing action of the PS-1 mutations. Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.
Guo
Q
Q
Sanders-Brown Research Center on Aging and Department of Anatomy & Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Fu
W
W
Holtsberg
F W
FW
Steiner
S M
SM
Mattson
M P
MP
D000544:Alzheimer Disease / Q000235:genetics; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002883:Chromosomes, Human, Pair 14; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D053764:Presenilin-1; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D016229:Amyloid beta-Peptides; D008563:Membrane Lipids; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase; D002118:Calcium