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

Oxidative stress is involved in the pathogenesis of neurodegeneration. Amyloid beta (A beta) 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 A beta 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 A beta production from hAPP as promising therapeutics, but the relationship between oxidative stress and A beta metabolism remains unclear. Here we found that Sod1 deficiency enhanced beta-cleavage of hAPP, suggesting that it increased A beta production in hAPP/Sod1(-/-) mice. In contrast, A beta 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 A beta production as well as aggregation during AD progression.