Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease.
Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease.
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DOI：
10.3233/jad-2006-9209
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
S. M. de la Monte;J. Wands
中科院分区：
文献类型：
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作者：
S. M. de la Monte;J. Wands
大脑中葡萄糖的摄取和能量代谢受胰岛素和胰岛素样生长因子（IGF）的调节。最近的研究表明，大脑胰岛素和IGF的生产和反应性进行性缺陷，并将这些异常与阿尔茨海默病（AD）中的乙酰胆碱缺乏症联系起来。我们通过尝试将胰岛素/IGF信号传导和能量产生的缺陷与不同Braak阶段AD严重程度的脑中线粒体功能障碍、氧化损伤和代偿性细胞保护反应相关联来扩展这一研究路线。额叶组织的真实的时间定量RT-PCR分析表明，显著降低的表达，与编码复合体I，II和III的基因的相对保存的MARA编码的复合体IV和V基因。此外，AD与p53促凋亡基因、一氧化氮合酶（NOS 1-3）的所有3种亚型以及NADPH氧化酶（NOX）1和NOX 3的表达显著增加相关，这些表达在疾病过程的早期开始。AD脑中细胞保护机制的激活受到限制，因为解偶联蛋白（UCP）2、4和5以及过氧化物酶体增殖物激活受体（PPAR）α和δ基因的表达水平显著降低，而PPAR-gamma表达选择性增加。结果表明，AD与氧化应激的分子指标的早期和显著增加有关，包括NOS和NOX基因的上调，这可能会损害电子传递链中复合物IV和V的功能。细胞保护机制（UCP和PPAR）的同时减少可能会使氧化损伤不受控制，并随着时间的推移持续或增加。因此，采取相应的措施降低NOS和NOX活性，改善UCPs和PPARs的作用，可能有助于AD的治疗。
Glucose uptake and energy metabolism in the brain are regulated by insulin and insulin-like growth factors (IGF). Recent studies demonstrated progressive deficiencies in brain insulin and IGF production and responsiveness, and linked these abnormalities to acetylcholine deficiency in Alzheimer's disease (AD). We extended this line of research by attempting to correlate the deficits in insulin/IGF signaling and energy production with mitochondrial dysfunction, oxidative injury, and compensatory cyto-protective responses in brains with different Braak Stage severities of AD. Real time quantitative RT-PCR analysis of frontal lobe tissue demonstrated significantly reduced expression of mitochondria-encoded Complex IV and V genes, with relative preservation of genes encoding Complexes I, II and III. In addition, AD was associated with significantly increased expression of the p53 pro-apoptosis gene, all 3 isoforms of nitric oxide synthase (NOS 1-3), and NADPH-oxidase (NOX) 1 and NOX 3, beginning early in the course of disease. Activation of cyto-protective mechanisms in AD brains was limited since the expression levels of uncoupling protein (UCP) 2, 4, and 5, and peroxisome-proliferator activated receptor (PPAR) alpha and delta genes were significantly reduced, whereas PPAR-gamma expression was selectively increased. The results demonstrate that AD is associated with early and striking increases in the molecular indices of oxidative stress, including up-regulation of NOS and NOX genes, which could impair the function of Complexes IV and V within the electron transport chain. The simultaneous reductions in cyto-protective mechanisms (UCP and PPAR), could allow oxidative injury to go unchecked and persist or increase over time. Adopting strategies to reduce the effects of NOS and NOX activities, and improve the actions of UCPs and PPARs may help in the treatment of AD.