Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer's disease.
Alzheimer's disease is a multifactorial, progressive, age-related neurodegenerative disease. In familial Alzheimer's disease, Abeta is excessively produced and deposited because of mutations in the amyloid precursor protein, presenilin-1, and presenilin-2 genes. Here, we generated a double homozygous knock-in mouse model that incorporates the Swedish familial Alzheimer's disease mutations and converts mouse Abeta to the human sequence in amyloid precursor protein and had the P264L familial Alzheimer's disease mutation in presenilin-1. We observed Abeta deposition in double knock-in mice beginning at 6 months as well as an increase in the levels of insoluble Abeta1-40/1-42. Brain homogenates from 3-, 6-, 9-, 12-, and 14-month-old mice showed that protein levels of manganese superoxide dismutase (MnSOD) were unchanged in the double knock-in mice compared to controls. Genotype-associated increases in nitrotyrosine levels were observed. Protein immunoprecipitation revealed MnSOD as a target of this nitration. Although the levels of MnSOD protein did not change, MnSOD activity and mitochondrial respiration decreased in knock-in mice, suggesting compromised mitochondrial function. The compromised activity of MnSOD, a primary antioxidant enzyme protecting mitochondria, may explain mitochondrial dysfunction and provide the missing link between Abeta-induced oxidative stress and Alzheimer's disease.
Anantharaman
Muthuswamy
M
Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0305, USA.
Tangpong
Jitbanjong
J
Keller
Jeffery N
JN
Murphy
Michael P
MP
Markesbery
William R
WR
Kiningham
Kelley K
KK
St Clair
Daret K
DK
D000375:Aging; D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D012119:Respiration; D013482:Superoxide Dismutase / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D016229:Amyloid beta-Peptides; C002744:3-nitrotyrosine; D014443:Tyrosine; D013482:Superoxide Dismutase