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(American Journal of Pathology. 2006;168:1608-1618.)
© 2006 American Society for Investigative Pathology

ß-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

Muthuswamy Anantharaman*, Jitbanjong Tangpong*{dagger}, Jeffery N. Keller{ddagger}§, Michael P. Murphy, William R. Markesbery{ddagger}||, Kelley K. Kiningham** and Daret K. St. Clair*

From the Graduate Center for Toxicology,* the Sanders Brown Center on Aging,{ddagger} and the Departments of Anatomy and Neurobiology,§ Molecular and Cellular Biochemistry, and Pathology and Neurology,|| University of Kentucky, Lexington, Kentucky; the Department of Pharmacology,** Marshall University, Huntington, West Virginia; and the Faculty of Medicine,{dagger} Prince of Songkhla University, Songkhla, Thailand

Alzheimer’s disease is a multifactorial, progressive, age-related neurodegenerative disease. In familial Alzheimer’s disease, Aß 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 Aß to the human sequence in amyloid precursor protein and had the P264L familial Alzheimer’s disease mutation in presenilin-1. We observed Aß deposition in double knock-in mice beginning at 6 months as well as an increase in the levels of insoluble Aß1-40/1-42. 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 Aß-induced oxidative stress and Alzheimer’s disease.




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