Parkinson's disease (PD) develops over decades through spatiotemporal stages that ascend from the brainstem to the forebrain. The mechanism behind this caudo-rostral neurodegeneration remains largely undefined. In unraveling this phenomenon, we recently developed a lipopolysaccharide (LPS)-elicited chronic neuroinflammatory mouse model that displays sequential losses of neurons in brainstem, substantia nigra, hippocampus and cortex. In this study, we aimed to investigate the mechanisms of caudo-rostral neurodegeneration and focused our efforts on the earliest neurodegeneration of vulnerable noradrenergic locus coeruleus (NE-LC) neurons in the brainstem. We found that compared with neurons in other brain regions, NE-LC neurons in untreated mice displayed high levels of mitochondrial oxidative stress that was severely exacerbated in the presence of LPS-elicited chronic neuroinflammation. In agreement, NE-LC neurons in LPS-treated mice displayed early reduction of complex IV expression and mitochondrial swelling and loss of cristae. Mechanistically, the activation of the superoxide-generating enzyme NADPH oxidase (NOX2) on NE-LC neurons was essential for their heightened vulnerability during chronic neuroinflammation. LPS induced early and high expressions of NOX2 in NE-LC neurons. Genetic or pharmacological inactivation of NOX2 markedly reduced mitochondrial oxidative stress and dysfunction in LPS-treated mice. Furthermore, inhibition of NOX2 significantly ameliorated LPS-induced NE-LC neurodegeneration. More importantly, post-treatment with NOX2 inhibitor diphenyleneiodonium when NE-LC neurodegeneration had already begun, still showed high efficacy in protecting NE-LC neurons from degeneration in LPS-treated mice. This study strongly supports that chronic neuroinflammation and NOX2 expression among vulnerable neuronal populations contribute to caudo-rostral degeneration in PD.

中文翻译：

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蓝斑神经元对慢性神经炎症诱导的神经变性最敏感

帕金森病 (PD) 的发展经历了从脑干到前脑的时空阶段。这种尾端神经变性背后的机制在很大程度上仍未确定。为了解开这一现象，我们最近开发了一种脂多糖 (LPS) 引发的慢性神经炎症小鼠模型，该模型显示脑干、黑质、海马和皮层中神经元的连续丢失。在这项研究中，我们旨在研究尾端神经变性的机制，并将我们的努力集中在脑干中易受伤害的去甲肾上腺素能蓝斑 (NE-LC) 神经元最早的神经变性上。我们发现，与其他大脑区域的神经元相比，未经治疗的小鼠中的 NE-LC 神经元表现出高水平的线粒体氧化应激，在 LPS 引起的慢性神经炎症的存在下，这种氧化应激会严重恶化。一致地，LPS 治疗的小鼠中的 NE-LC 神经元表现出复合体 IV 表达的早期减少和线粒体肿胀和嵴的丢失。从机制上讲，NE-LC 神经元上产生超氧化物的酶 NADPH 氧化酶 (NOX2) 的激活对于它们在慢性神经炎症期间的脆弱性增加至关重要。LPS 诱导 NE-LC 神经元中 NOX2 的早期和高表达。NOX2 的遗传或药理学失活显着降低了 LPS 治疗小鼠的线粒体氧化应激和功能障碍。此外，抑制 NOX2 可显着改善 LPS 诱导的 NE-LC 神经变性。更重要的是，当 NE-LC 神经变性已经开始时，用 NOX2 抑制剂二亚苯基碘进行后处理，在保护 LPS 治疗小鼠的 NE-LC 神经元免于变性方面仍然表现出高效。这项研究强烈支持脆弱神经元群中的慢性神经炎症和 NOX2 表达导致 PD 的尾端退化。