Oxidative damage in brain from human mutant APP/PS-1 double knock-in mice as a function of age

• Published in: Free radical biology & medicine 2008-11, Vol.45 (10), p.1420-1425
• Main Authors: Abdul, Hafiz Mohmmad, Sultana, Rukhsana, St Clair, Daret K, Markesbery, William R, Butterfield, D Allan
• Format: Article
• Language: English
• Subjects: Aging - physiology; Aldehydes - metabolism; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Brain - metabolism; Humans; Lipid Peroxidation; Mice; Mice, Mutant Strains; Mutation; Oxidative Stress; Peptide Fragments - metabolism; Presenilin-1 - genetics; Presenilin-1 - metabolism; Protease Nexins; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism
• ISSN: 0891-5849
• DOI: 10.1016/j.freeradbiomed.2008.08.012

Oxidative stress is strongly implicated in the progressive decline of cognition associated with aging and neurodegenerative disorders. In the brain, free radical-mediated oxidative stress plays a critical role in the age-related decline of cellular function as a result of the oxidation of proteins, lipids, and nucleic acids. A number of studies indicate that an increase in protein oxidation and lipid peroxidation is associated with age-related neurodegenerative diseases and cellular dysfunction observed in aging brains. Oxidative stress is one of the important factors contributing to Alzheimer's disease (AD), one of whose major hallmarks includes brain depositions of amyloid beta-peptide (Abeta) derived from amyloid precursor protein (APP). Mutation in APP and PS-1 genes, which increases production of the highly amyloidogenic amyloid beta-peptide (Abeta42), is the major cause of familial AD. In the present study, protein oxidation and lipid peroxidation in the brain from knock-in mice expressing human mutant APP and PS-1 were compared with brain from wild type, as a function of age. The results suggest that there is an increased oxidative stress in the brain of wild-type mice as a function of age. In APP/PS-1 mouse brain, there is a basal increase (at 1 month) in oxidative stress compared to the wild type (1 month), as measured by protein oxidation and lipid peroxidation. In addition, age-related elevation of oxidative damage was observed in APP/PS-1 mice brain compared to that of wild-type mice brain. These results are discussed with reference to the importance of Abeta42-associated oxidative stress in the pathogenesis of AD.