309th Hospital of Chinese People's Liberation Army, Beijing, China.
Gerontology. 2012;58(1):62-9. doi: 10.1159/000327821. Epub 2011 Sep 7.
Oxidative stress (OS) may be involved in the neurodegenerative process in Alzheimer's disease (AD). Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, are sensitive to OS, and serve as markers of a cell's replicative history. Telomere length shortening has been reported to relate to OS with aging process and aging-associated diseases, but the telomeric changes were not always identical, especially in change of telomere length distribution and subtelomeric methylation. The involvement of an OS-associated telomere change in the pathogenesis of AD has been discussed for decades, and the telomere length and telomerase activity were analyzed. However, other telomeric factors, such as the telomere distribution and subtelomeric methylation status, have not yet been analyzed.
The subtelomeric methylation status as well as the telomere length were studied in AD with an antioxidant vitamin in terms of OS.
We measured urinary 8-iso-PGF2α, a lipid-peroxidation product as an OS marker, and methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells by Southern blotting in AD patients before and after vitamin E treatment.
The level of urinary 8-iso-PGF2α was found to have increased in AD. Middle-ranged telomeres (4.4-9.4 kb) increased and the shortest telomeres (<4.4 kb) decreased in AD patients. Telomeres were more methylated in both long telomeres and in short telomeres in AD compared with the control. The oral administration of the antioxidant vitamin E in 400 mg/day for 6 months in AD patients partly reversed AD-associated alterations in OS marker levels.
AD patients showed an elevated OS marker level, and vitamin E lowered the OS level. In comparison with controls, AD patients showed shorter telomere lengths. Cells with short and long telomeres bore relatively hypermethylated subtelomeres in AD patients. Aging-associated accumulation of cells bearing short telomeres was not observed in AD. These results imply that long telomeres with hypomethylation tend to shorten faster, and cells bearing short telomeres with hypomethylation tend to more easily enter into a senescent state under elevated OS stress in AD. However, no significant effect on the altered telomeric profiles in AD patients could be detected after a 6-month administration of vitamin E.
氧化应激（OS）可能参与阿尔茨海默病（AD）的神经退行性过程。端粒是染色体末端的重复序列，随着细胞分裂而缩短，对 OS 敏感，并且是细胞复制历史的标志物。已经报道端粒长度缩短与衰老过程和与衰老相关的疾病中的 OS 有关，但是端粒变化并不总是相同的，尤其是在端粒长度分布和亚端粒甲基化的变化。OS 相关端粒变化在 AD 发病机制中的参与已经讨论了几十年，并且分析了端粒长度和端粒酶活性。然而，其他端粒因素，例如端粒分布和亚端粒甲基化状态，尚未得到分析。
在抗氧化维生素的情况下，针对 OS 研究 AD 中的亚端粒甲基化状态和端粒长度。
我们通过Southern 印迹法测量了 AD 患者在接受维生素 E 治疗前后外周血单个核细胞中的尿 8-异前列腺素 F2α（一种 OS 标志物）、甲基化和非甲基化的端粒长度。
发现 AD 患者的尿 8-异前列腺素 F2α 水平升高。AD 患者的中等端粒（4.4-9.4 kb）增加，最短端粒（<4.4 kb）减少。与对照组相比，AD 患者的长端粒和短端粒的端粒都更甲基化。AD 患者每天口服抗氧化维生素 E 400 mg，持续 6 个月，部分逆转了 AD 相关的 OS 标志物水平变化。
AD 患者表现出升高的 OS 标志物水平，而维生素 E 降低了 OS 水平。与对照组相比，AD 患者的端粒较短。AD 患者的短端粒和长端粒细胞带有相对过度甲基化的亚端粒。在 AD 中，没有观察到与衰老相关的短端粒细胞的积累。这些结果表明，在 AD 中，低甲基化的长端粒更容易缩短，而在 OS 应激升高的情况下，更容易进入衰老状态的短端粒细胞的端粒较短。然而，在 AD 患者中，经过 6 个月的维生素 E 治疗后，并未检测到端粒谱的明显变化。
