Aging‐related increase in oxidative stress correlates with developmental pattern of beta‐secretase activity and beta‐amyloid plaque formation in transgenic Tg2576 mice with Alzheimer‐like pathology
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Medientyp:
E-Artikel
Titel:
Aging‐related increase in oxidative stress correlates with developmental pattern of beta‐secretase activity and beta‐amyloid plaque formation in transgenic Tg2576 mice with Alzheimer‐like pathology
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>The molecular mechanisms of β‐amyloidogenesis in sporadic Alzheimer's disease are still poorly understood. To reveal whether aging‐associated increases in brain oxidative stress and inflammation may trigger onset or progression of β‐amyloid deposition, a transgenic mouse (Tg2576) that express the Swedish double mutation of human amyloid precursor protein (APP) was used as animal model to study the developmental pattern of markers of oxidative stress and APP processing. In Tg2576 mouse brain, cortical levels of soluble β‐amyloid (1–40) and (1–42) steadily increased with age, but significant deposition of fibrillary β‐amyloid in cortical areas did not occur before postnatal age of 10 months. The slope of increase in cerebral cortical β‐secretase (BACE1) activities in Tg2576 mice between ages of 9 and 13 months was significantly higher as compared to that of the α‐secretase, while the expression level of BACE1 protein and mRNA did not change with age. The activities of superoxide dismutase and glutathione peroxidase in cortical tissue from Tg2576 mice steadily increased from postnatal age 9–12 months. The levels of cortical nitric oxide, and reactive nitrogen species demonstrated peak values around 9 months of age, while the level of interleukin‐1β steadily increased from postnatal month 13 onwards. The developmental temporal coincidence of increased levels of reactive nitrogen species and antioxidative enzymes with the onset of β‐amyloid plaque deposition provides further evidence that developmentally and aging‐induced alterations in brain oxidative status exhibit a major factor in triggering enhanced production and deposition of β‐amyloid, and potentially predispose to Alzheimer's disease.</jats:p></jats:sec>