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

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2012, Vol.76 (6), p.1098-1103
• Main Authors: MURAKAMI, Kazuma, MURATA, Nakaba, NODA, Yoshihiro, IRIE, Kazuhiro, SHIRASAWA, Takuji, SHIMIZU, Takahiko
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; amyloid β; Animals; Biological and medical sciences; Brain - metabolism; Brain - pathology; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Glutathione - metabolism; Humans; Mice; Mice, Transgenic; Oxidation-Reduction; oxidative stress; Oxidative Stress - genetics; Protein Carbonylation; Proteolysis; Signal Transduction - genetics; superoxide dismutase (SOD); Superoxide Dismutase - deficiency; Superoxide Dismutase - genetics; Superoxide Dismutase-1; superoxide radical
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1271/bbb.110934

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.