Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer’s disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques. For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden. Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

中文翻译：

---

线粒体氧化还原的实时成像揭示了阿尔茨海默病小鼠模型中与体内β淀粉样蛋白聚集相关的线粒体氧化应激增加

反应性氧化应激是β淀粉样蛋白（Aβ）毒性的一个关键因素，它会导致阿尔茨海默病（AD）的神经退行性变。受损的线粒体是活性氧的主要来源之一，并在 AD 大脑中与 Aβ 斑块相关的营养不良性神经突中积累。尽管 Aβ 在体外会引起神经元线粒体反应性氧化应激，但从未在活体小鼠大脑中直接观察到这种情况。在这里，我们首次测试了 Aβ 斑块和可溶性 Aβ 寡聚物是否会在体内诱导周围神经元的线粒体氧化应激，以及是否可以使用线粒体靶向抗氧化剂消除这种神经毒性作用。我们在该疾病的小鼠模型中表达了基因编码的荧光比率线粒体靶向氧化应激报告基因，并对神经元线粒体和 Aβ 斑块进行了活体多光子显微镜检查。我们首次通过在活体小鼠大脑中的直接观察证明，Aβ斑块沉积和可溶性寡聚Aβ直接应用到大脑后会加剧神经元中的线粒体氧化应激，并确定导致氧化应激的最可能的病理事件顺序体内。通过阻止钙流入线粒体和用线粒体靶向抗氧化剂 SS31 进行治疗，可以抑制氧化应激。值得注意的是，后者改善了斑块相关的营养不良性神经突，而不影响 Aβ 斑块负担。考虑到这些结果，线粒体靶向化合物与其他抗淀粉样蛋白 β 或抗 tau 疗法的组合有望作为预防和/或治疗 AD 的神经保护药物。