β-amyloid mediated nitration of manganese superoxide dismutase: Implication for oxidative stress in a APPNLh/NLh X PS-1 P264L/P264L double knock-in mouse model of Alzheimer's disease

Muthuswamy Anantharaman, Jitbanjong Tangpong, Jeffery N. Keller, Michael P. Murphy, William R. Markesbery, Kelley K. Kiningham, Daret K. St. Clair

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

Alzheimer's disease is a multifactorial, progressive, age-related neurodegenerative disease. In familial Alzheimer's disease, Aβ 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 Aβ to the human sequence in amyloid precursor protein and had the P264L familial Alzheimer's disease mutation in presenilin-1. We observed Aβ deposition in double knock-in mice beginning at 6 months as well as an increase in the levels of insoluble Aβ1-40/1-42. 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 Aβ-induced oxidative stress and Alzheimer's disease.

Original languageEnglish
Pages (from-to)1608-1618
Number of pages11
JournalAmerican Journal of Pathology
Volume168
Issue number5
DOIs
StatePublished - May 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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