Stimulation of the Amyloidogenic Pathway by Cytoplasmic Superoxide Radicals in an Alzheimer's Disease Mouse Model

Abstract

Oxidative stress is involved in the pathogenesis of neurodegeneration. Amyloid β (Aβ) oligomer as an intermediate of aggregates causes memory loss in Alzheimer's disease (AD). We have suggested that oxidative stress plays an important role in Aβ oligomerization and cognitive impairment using a human amyloid precursor protein (hAPP) transgenic AD mice lacking cytoplasmic superoxide dismutase (hAPP/Sod1 ^−/−). Recently, clinical trials revealed inhibitors of Aβ production from hAPP as promising therapeutics, but the relationship between oxidative stress and Aβ metabolism remains unclear. Here we found that Sod1 deficiency enhanced β-cleavage of hAPP, suggesting that it increased Aβ production in hAPP/Sod1 ^−/− mice. In contrast, Aβ degradation did not decrease in hAPP/Sod1 ^−/− as compared with hAPP/Sod1 ^+/+ mice. Furthermore, we successfully detected in situ superoxide radicals associated with increased protein carbonylation in hAPP/Sod1 ^−/−. These results suggest that cytoplasmic oxidative stress is involved in Aβ production as well as aggregation during AD progression.

• Alzheimer's disease
• amyloid β
• superoxide dismutase (SOD)
• superoxide radical
• oxidative stress