Oxidative modification of lipoic acid by HNE in Alzheimer disease brain.
Oxidative modification of lipoic acid by HNE in Alzheimer disease brain.
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DOI：
10.1016/j.redox.2013.01.002
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
--
作者：
Hardas, Santa S.;Sultana, Rukhsana;Clark, Amy M.;Beckett, Tina L.;Szweda, Luke I.;Murphy, M. Paul;Butterfield, D. Allan
关键词：
阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病，以突触丢失、细胞外老年斑(SP)和细胞内神经原纤维缠结(NFTs)三种病理特征为特征。SP的主要成分是淀粉样蛋白β-肽(A-β)，已被证明可诱导氧化应激。阿尔茨海默病患者大脑中的脂质过氧化产物水平升高，包括4-羟基-2-壬烯醛(HNE)。HNE能与蛋白质上的半胱氨酸、组氨酸或赖氨酸残基发生共价反应，改变后者的结构和功能。在本研究中，我们测量了AD患者和年龄匹配的对照组大脑中HNE修饰的硫辛酸的水平。硫辛酸是许多蛋白质的关键辅助因子，包括丙酮酸脱氢酶和α-酮戊二酸脱氢酶，这两种酶是细胞能量学的关键复合体。我们观察到，与年龄匹配的对照组相比，阿尔茨海默病患者大脑中的HNE-硫辛酸水平显著降低。为了进一步研究这一现象，我们测定了AD组和对照组脑组织中硫酰胺脱氢酶(LADH)的水平和活性。此外，还测定了体外HNE处理小鼠脑后的LADH活性。与年龄匹配的对照组相比，阿尔茨海默病患者大脑中的LASH水平和活性均显著降低。HNE还能降低小鼠脑组织中LASH的活性。这些数据与AD的两次打击假说是一致的：氧化应激导致脂质过氧化，进而导致线粒体中关键能量相关复合体的氧化功能障碍，引发神经退化。这项研究与以下观点是一致的，即硫辛酸补充可能是一种潜在的治疗AD细胞能量丧失的方法，并增强抗氧化防御系统，以防止或延缓这种毁灭性痴呆障碍的氧化应激和进展。NADH依赖的氧化还原酶硫酰胺脱氢酶(LADH)是线粒体能量产生复合体的重要成员。活性氧(ROS)升高引起的LADH结构和活性改变可能阻碍能量代谢和ATP的产生。硫辛酸(LA)必须以还原形式存在，作为线粒体三氯乙酸复合体(如α-酮戊二酸脱氢酶)的辅因子功能的一部分。然而，氧化型LADH不能将LA还原为DHL A，因此HNE不能与DHL A有效结合。因此，在这项研究中，观察到阿尔茨海默病患者大脑中LA-HNE结合减少。对学习、记忆和高级执行功能的严重影响在AD患者中都会显著丧失，这是可以预期的。可以想象，补充LA可能通过自我牺牲机制保护LADH免受ROS或ROS的最终产物(如HNE)的影响，潜在地提供对痴呆的保护或减缓AD的进展速度。►HNE结合的硫辛酸(HNE-LA)水平在AD脑内的IPL区降低。►是一种三氯乙酸酶，它能将非活性硫辛酸转化为活性抗氧化剂。阿尔茨海默病模型大鼠脑区►-LADH水平和活性明显降低。►体外对小鼠脑内HNE处理可降低LADH活性。►结果符合阿尔茨海默病的两次打击假说。
Alzheimer disease (AD) is an age-related neurodegenerative disease characterized by the presence of three pathological hallmarks: synapse loss, extracellular senile plaques (SP) and intracellular neurofibrillary tangles (NFTs). The major component of SP is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress. The AD brain shows increased levels of lipid peroxidation products, including 4-hydroxy-2-nonenal (HNE). HNE can react covalently with Cys, His, or Lys residues on proteins, altering structure and function of the latter. In the present study we measured the levels of the HNE-modified lipoic acid in brain of subjects with AD and age-matched controls. Lipoic acid is a key co-factor for a number of proteins including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, key complexes for cellular energetics. We observed a significant decrease in the levels of HNE-lipoic acid in the AD brain compared to that of age-matched controls. To investigate this phenomenon further, the levels and activity of lipoamide dehydrogenase (LADH) were measured in AD and control brains. Additionally, LADH activities were measured after in-vitro HNE-treatment to mice brains. Both LADH levels and activities were found to be significantly reduced in AD brain compared to age-matched control. HNE-treatment also reduced the LADH activity in mice brain. These data are consistent with a two-hit hypothesis of AD: oxidative stress leads to lipid peroxidation that, in turn, causes oxidative dysfunction of key energy-related complexes in mitochondria, triggering neurodegeneration. This study is consonant with the notion that lipoic acid supplementation could be a potential treatment for the observed loss of cellular energetics in AD and potentiate the antioxidant defense system to prevent or delay the oxidative stress in and progression of this devastating dementing disorder. The NADH-dependent oxido-reductase enzyme lipoamide dehydrogenase (LADH) is an important member of the mitochondrial energy generation complex. Alteration of the structure and activity of LADH by elevated reactive oxygen species (ROS) may hamper energy metabolism and ATP production. Lipoic acid (LA) must be in the reduced form as part of its co-factor function for mitochondrial TCA complexes such as α-ketoglutarate dehydrogenase. However, oxidized LADH is unable to reduce LA to DHLA, and therefore HNE is unable to bind to DHLA efficiently. Consequently, in this study, decreased LA-HNE binding was observed in Alzheimer disease brain. Severe effects on learning, memory, and higher executive functioning, all significantly lost in AD patients, would be expected. Supplementation of LA conceivably may protect LADH from ROS or end products of ROS (e.g., HNE) by self-sacrifice mechanism, potentially providing protection against dementia or slowing the rate of progression of AD. ► HNE-bound lipoic acid (HNE-LA) levels were decreased in the IPL region of AD brain. ► The TCA enzyme LADH converts inactive lipoic acid to its active-antioxidant form. ► LADH levels and activity were deceased in AD in IPL brain region. ► In-vitro HNE-treatment to mouse brain reduced LADH activity. ► The results fit the two-hit hypothesis of AD.
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影响因子：
5.8
作者：
Biewenga, GP;Dorstijn, MA;Bast, A
通讯作者：
Bast, A
DOI：
10.1016/s0925-4439(01)00091-6
发表时间：
2002-03-16
影响因子：
6.2
作者：
Gibson, GE;Zhang, H;Jeitner, TM
通讯作者：
Jeitner, TM
影响因子：
6.1
作者：
Kim, SH;Vlkolinsky, R;Lubec, G
通讯作者：
Lubec, G
影响因子：
2.9
作者：
Humphries, KM;Szweda, LI
通讯作者：
Szweda, LI
影响因子：
4.7
作者：
Klivenyi, P;Starkov, AA;Beal, MF
通讯作者：
Beal, MF