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 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.
Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Kazuma
K
Murakami
Nakaba
N
Murata
Yoshihiro
Y
Noda
Kazuhiro
K
Irie
Takuji
T
Shirasawa
Takahiko
T
Shimizu
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D050050:Protein Carbonylation; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics*; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D000072105:Superoxide Dismutase-1
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione