Cecarini Valentina, Ding Qunxing, Keller Jeffrey N
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Free Radic Res. 2007 Jun;41(6):673-80. doi: 10.1080/10715760701286159.
In the present study we isolated proteasome complexes from control, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects. No significant difference in the amount of proteasomes was detected across the different groups, although impairments in chymotrypsin-like proteasome activity was observed in AD subjects. Large impairments in proteasome- mediated degradation of an oxidized protein substrate was observed in MCI and AD subjects. Incubation with a reducing agent (DTT) had no significant effect on proteasome chymotrypsin-like activity, but fully restored proteasome-mediated protein degradation in MCI and AD subjects. Proteasomes from AD subjects exhibited elevations in protein carbonyls, 4-hydroxynonenal-conjugation, and neuroprostane-conjugation. Together, these data confirm that impairments in the function of purified proteasomes occurs in the earliest stages of AD, and directly support a role for oxidative inactivation contributing to declines in proteasome function in AD.
在本研究中，我们从对照、轻度认知障碍（MCI）和阿尔茨海默病（AD）受试者中分离出蛋白酶体复合物。尽管在AD受试者中观察到胰凝乳蛋白酶样蛋白酶体活性受损，但不同组之间蛋白酶体的量未检测到显著差异。在MCI和AD受试者中观察到蛋白酶体介导的氧化蛋白底物降解存在较大损伤。用还原剂（二硫苏糖醇，DTT）孵育对蛋白酶体胰凝乳蛋白酶样活性没有显著影响，但完全恢复了MCI和AD受试者中蛋白酶体介导的蛋白质降解。AD受试者的蛋白酶体表现出蛋白质羰基、4-羟基壬烯醛缀合物和神经前列腺素缀合物的升高。总之，这些数据证实纯化的蛋白酶体功能受损发生在AD的最早阶段，并直接支持氧化失活在AD蛋白酶体功能下降中起作用。
