Murakami Kazuma, Murata Nakaba, Noda Yoshihiro, Irie Kazuhiro, Shirasawa Takuji, Shimizu Takahiko
Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Biosci Biotechnol Biochem. 2012;76(6):1098-103. doi: 10.1271/bbb.110934. Epub 2012 Jun 7.
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.
氧化应激参与神经退行性变的发病机制。淀粉样β（Aβ）寡聚体作为聚集体的中间体，会导致阿尔茨海默病（AD）患者出现记忆丧失。我们曾提出，利用缺乏胞质超氧化物歧化酶的人淀粉样前体蛋白（hAPP）转基因AD小鼠（hAPP/Sod1-/-），氧化应激在Aβ寡聚化和认知障碍中起重要作用。最近，临床试验表明，hAPP来源的Aβ生成抑制剂是很有前景的治疗方法，但氧化应激与Aβ代谢之间的关系仍不清楚。在此，我们发现Sod1缺陷增强了hAPP的β切割，这表明它增加了hAPP/Sod1-/-小鼠的Aβ生成。相比之下，与hAPP/Sod1+/+小鼠相比，hAPP/Sod1-/-小鼠的Aβ降解并未减少。此外，我们成功地在hAPP/Sod1-/-小鼠中检测到与蛋白质羰基化增加相关的原位超氧自由基。这些结果表明，在AD进展过程中，胞质氧化应激参与了Aβ的生成以及聚集。
