A lead study on oxidative stress-mediated dehydroepiandrosterone formation in serum: the biochemical basis for a diagnosis of Alzheimer's disease.
A lead study on oxidative stress-mediated dehydroepiandrosterone formation in serum: the biochemical basis for a diagnosis of Alzheimer's disease.
复制标题
DOI：
10.3233/jad-2011-101941
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
G. Rammouz;L. Lecanu;P. Aisen;V. Papadopoulos
中科院分区：
文献类型：
--
作者：
G. Rammouz;L. Lecanu;P. Aisen;V. Papadopoulos
阿尔茨海默病(AD)是一种进行性但不可逆转的神经退行性疾病，其生前诊断手段有限。我们以前在大鼠、牛和人脑中发现了一种脑和细胞特异性的氧化应激介导的脱氢表雄酮生物合成机制，这种机制独立于外周发现的细胞色素P45017-羟基酶/17，20-裂解酶(α17)活性。这种替代途径是由促氧化剂诱导的，如Fe2+和淀粉样蛋白-β肽。使用来自对照组和AD患者的脑组织样本，我们随后提供了证据，表明DHEA是通过氧化应激介导的不明前体的代谢在AD大脑中形成的，从而耗尽了血流中存在的前体的水平。在这里，我们通过一种简单的基于Fe2+的反应来检测人血清中DHEA前体的存在，并确定了DHEA的生成量。这项研究共纳入86名受试者：19名男性和20名女性AD患者；18名男性和22名女性年龄匹配的对照组；4名男性和3名女性轻度认知障碍。在对照组，血清氧化导致DHEA水平显著升高，而在AD患者中仅观察到中度或无升高。氧化后脱氢表雄酮的变化与患者的认知和心理状态有关。这些结果表明，比较氧化前后患者血清中DHEA的水平可以为AD的诊断提供有用的工具。
Alzheimer's disease (AD) is a progressive, yet irreversible, neurodegenerative disease for which there are limited means for its ante-mortem diagnosis. We previously identified a brain- and cell-specific oxidative stress-mediated mechanism for dehydroepiandrosterone (DHEA) biosynthesis present in rat, bovine, and human brain, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and amyloid-β peptide. Using brain tissue specimens from control and AD patients we subsequently provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting the levels of the precursor present in the blood stream. Here, we tested for the presence of this DHEA precursor in human serum using a simple Fe2+-based reaction and determined the amounts of DHEA formed. A total of 86 subjects were included in this study: 19 male and 20 female AD patients; 18 male and 22 female age-matched controls; and 4 men and 3 women with mild cognitive impairment. Serum oxidation resulted in a dramatic increase of DHEA level in control patients, whereas only a moderate or no increase was observed in the AD patients. The DHEA variation after oxidation correlated with the patients' cognitive and mental status. These results suggest that the comparison of DHEA levels in patient serum before and after oxidation could provide a useful tool to diagnose AD.