β-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, A beta 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 A beta to the human sequence in amyloid precursor protein and had the P264L familial Alzheimer's disease mutation in presenilin-1. We observed A beta deposition in double knock-in mice beginning at 6 months as well as an increase in the levels of insoluble A beta 1-40/ 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 A beta-induced oxidative stress and Alzheimer's disease.