Oxidative stress, likely stemming from dysfunctional mitochondria, occurs before major cognitive deficits and neuropathologies become apparent in Alzheimer's disease (AD) patients and in mouse models of the disease. We previously reported that treating 2- to 7-month-old 3xTg-AD mice with the mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl](triphenyl)phosphonium methanesulfonate), a period when AD-like pathologies first manifest in them, prevents AD-like symptoms from developing. To elucidate further a role for mitochondria-derived oxidative stress in AD progression, we examined the ability of MitoQ to inhibit AD-like pathologies in these mice at an age in which cognitive and neuropathological symptoms have fully developed. 3xTg-AD female mice received MitoQ in their drinking water for five months beginning at twelve months after birth. Untreated 18-month-old 3xTg-AD mice exhibited significant learning deficits and extensive AD-like neuropathologies. MitoQ-treated mice showed improved memory retention compared to untreated 3xTg-AD mice as well as reduced brain oxidative stress, synapse loss, astrogliosis, microglial cell proliferation, Aβ accumulation, caspase activation, and tau hyperphosphorylation. Additionally, MitoQ treatment significantly increased the abbreviated lifespan of the 3xTg-AD mice. These findings support a role for the involvement of mitochondria-derived oxidative stress in the etiology of AD and suggest that mitochondria-targeted antioxidants may lessen symptoms in AD patients.

中文翻译：

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线粒体靶向抗氧化剂 MitoQ 可抑制老年 3xTg-AD 小鼠的记忆丧失、神经病理学并延长其寿命。

氧化应激可能源于线粒体功能障碍，发生在阿尔茨海默病 (AD) 患者和该疾病的小鼠模型中的主要认知缺陷和神经病理学变得明显之前。我们之前曾报道，用靶向线粒体的抗氧化剂 MitoQ（甲磺酸米托醌：[10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1, 4-环己二烯-1-基）癸基]（三苯基）鏻甲磺酸盐），即 AD 样病变首次出现的时期，可防止 AD 样症状的发展。为了进一步阐明线粒体衍生的氧化应激在 AD 进展中的作用，我们检查了 MitoQ 在认知和神经病理学症状完全发展的年龄抑制这些小鼠中 AD 样病变的能力。从出生后 12 个月开始，3xTg-AD 雌性小鼠在饮用水中接受 MitoQ，持续五个月。未经治疗的 18 个月大的 3xTg-AD 小鼠表现出明显的学习缺陷和广泛的 AD 样神经病变。与未经处理的 3xTg-AD 小鼠相比，经 MitoQ 处理的小鼠表现出更好的记忆力保留，以及减少的脑氧化应激、突触丢失、星形胶质细胞增生、小胶质细胞增殖、Aβ 积累、半胱天冬酶激活和 tau 过度磷酸化。此外，MitoQ 治疗显着增加了 3xTg-AD 小鼠的缩短寿命。这些发现支持线粒体衍生的氧化应激在 AD 病因学中的作用，并表明针对线粒体的抗氧化剂可能会减轻 AD 患者的症状。