The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease.
The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease.
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DOI：
10.1523/jneurosci.0552-11.2011
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发表时间：
2011-11-02
期刊：
影响因子：
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通讯作者：
Franklin JL
中科院分区：
文献类型：
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作者：
McManus MJ;Murphy MP;Franklin JL
大量证据表明，线粒体功能障碍和氧化应激会导致阿尔茨海默病 (AD) 的进展。我们研究了新型线粒体靶向抗氧化剂 MitoQ（甲磺酸线粒体醌：[10-(4,5-二甲氧基-2-甲基-3,6-二氧代-1,4-环己二烯基）癸基三苯基甲磺酸盐]）在细胞培养物和小鼠皮质神经元中预防 AD 样病理的能力。 AD (3xTg-AD) 的三重转基因小鼠模型。 MitoQ 减弱了 β-淀粉样蛋白 (Aβ) 诱导的皮层神经元的神经毒性，并防止其中活性物质的产生增加和线粒体膜电位 (Δψm) 的损失。为了确定 MitoQ 赋予的线粒体保护是否足以预防体内 AD 样神经病理学的出现，我们用 MitoQ 治疗年轻雌性 3xTg-AD 小鼠 5 个月，并分析其对 AD 样病理学进展的影响。我们的结果表明，MitoQ 可以防止这些小鼠的认知能力下降，以及大脑中的氧化应激、Aβ 积累、星形胶质细胞增生、突触损失和 caspase 激活。本文提出的工作表明线粒体在神经变性中发挥着核心作用，并提供了支持在涉及氧化应激和代谢衰竭的疾病（即 AD）中使用线粒体靶向疗法的证据。
Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimer’s disease (AD). We examined the ability of the novel mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienlyl) decyl triphenylphosphonium methanesulfonate]) to prevent AD-like pathology in mouse cortical neurons in cell culture and in a triple transgenic mouse model of AD (3xTg-AD). MitoQ attenuated β-amyloid (Aβ)-induced neurotoxicity in cortical neurons and also prevented increased production of reactive species and loss of mitochondrial membrane potential (Δψm) in them. To determine whether the mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-like neuropathology in vivo, we treated young female 3xTg-AD mice with MitoQ for 5 months and analyzed the effect on the progression of AD-like pathologies. Our results show that MitoQ prevented cognitive decline in these mice as well as oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in their brains. The work presented herein suggests a central role for mitochondria in neurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely AD.