Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB, Canada; Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, MB, Canada.
Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre, Winnipeg, MB, Canada.
Neuroscience. 2017 Oct 11;361:81-92. doi: 10.1016/j.neuroscience.2017.08.006. Epub 2017 Aug 9.
Alzheimer's disease (AD) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid β (Aβ). It was suggested that one of the possible mediators for Aβ-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-κB signaling in AD brain. In this study, we looked for sex-based differences in impaired bioenergetic processes and NF-κB signaling in the AD-like brain using transgenic (Tg) CRND8 mice that express excessive brain Aβ, but without tau pathology. Our results show that mitochondrial dysfunction is not uniform in affected brain regions. We observed increased basal and coupled respiration in the hippocampus of TgCRND8 females only, along with a decreased Complex II-dependent respiratory activity. Cortical mitochondria from TgCRND8 mice have reduced uncoupled respiration capacity, regardless of sex. The pattern of changes in NF-κB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF-κB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies.
阿尔茨海默病（AD）是最常见的迟发性神经退行性疾病，有迹象表明女性受影响的比例不成比例。线粒体功能障碍是与 AD 的早期发病和进展最相关的假说之一，并且归因于淀粉样β（Aβ）在神经元内的积累。有人认为，Aβ损害线粒体功能的可能介导物之一是核因子 kappa B（NF-κB）信号通路。NF-κB 在大脑炎症和抗氧化防御以及调节线粒体功能方面发挥着重要作用，并且研究已经证实 AD 大脑中的 NF-κB 信号发生改变。在这项研究中，我们使用表达过量脑 Aβ但没有 tau 病理学的转基因（Tg）CRND8 小鼠，寻找 AD 样脑中受损生物能过程和 NF-κB 信号的性别差异。我们的结果表明，线粒体功能障碍在受影响的脑区并不均匀。我们仅在 TgCRND8 雌性小鼠的海马体中观察到基础和偶联呼吸增加，同时伴有 II 型复合物依赖性呼吸活性降低。无论性别如何，来自 TgCRND8 小鼠的皮质线粒体的解偶联呼吸能力都降低了。NF-κB 信号变化的模式在两种脑结构中相同，但具有性别特异性。尽管在女性中所有三种 NF-κB 亚基都增加，但在男性中我们观察到 p65 和 p105 增加，而 p50 水平没有变化。这些结果表明，AD 样脑中的线粒体功能和炎症信号具有区域和性别特异性，这是治疗策略的重要考虑因素。
