Mitochondrial oxidative stress causes hyperphosphorylation of tau.
Mitochondrial oxidative stress causes hyperphosphorylation of tau.
复制标题
线粒体氧化应激会导致tau的过度磷酸化。
DOI：
10.1371/journal.pone.0000536
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发表时间：
2007-06-20
期刊：
影响因子：
3.7
通讯作者：
Bush, Ashley I.
中科院分区：
文献类型：
--
作者：
Melov, Simon;Adlard, Paul A.;Morten, Karl;Johnson, Felicity;Golden, Tamara R.;Hinerfeld, Doug;Schilling, Birgit;Mavros, Christine;Masters, Colin L.;Volitakis, Irene;Li, Qiao-Xin;Laughton, Katrina;Hubbard, Alan;Cherny, Robert A.;Gibson, Brad;Bush, Ashley I.
与神经退行性疾病相关的神经退行性疾病已经通过细胞内产生的活性氧的损伤与线粒体功能障碍机械地联系在一起。我们确定增加的线粒体氧化应激是否可以调节或调节阿尔茨海默病（AD）的两个关键神经化学标志：tau蛋白磷酸化和β-淀粉样蛋白沉积。缺乏超氧化物歧化酶2（SOD 2）的小鼠在出生后第一周内死亡，并发展出由线粒体功能障碍和氧化应激引起的复杂异质表型。用催化抗氧化剂治疗这些小鼠可以延长它们的寿命，挽救外周表型，同时揭示中枢神经系统病理学。我们检查了用高剂量和低剂量的催化抗氧化剂差异处理的sod 2裸小鼠，并观察到低剂量抗氧化剂处理的小鼠中AD相关残基的tau磷酸化水平（在Ser-396和tau的其他磷酸化表位）显著升高。这种tau蛋白的过度磷酸化可以通过增加抗氧化剂的剂量来防止，先前报道足以防止神经病理学。然后，我们在遗传学上结合了一个良好表征的AD小鼠模型（Tg 2576）与杂合sod 2基因敲除小鼠，以研究线粒体氧化应激和脑ApoE负荷之间的相互作用。我们发现，线粒体SOD 2缺乏加剧了淀粉样蛋白的负担，并显着降低金属水平在大脑中，同时增加水平的Ser-396磷酸化tau。这些发现将线粒体氧化应激与AD的病理特征机械地联系起来。
Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and ß-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Aß load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.
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