Bayer Schering Pharma AG, Berlin, Germany.
Neurochem Int. 2010 Nov;57(4):375-82. doi: 10.1016/j.neuint.2010.02.001. Epub 2010 Feb 6.
Degeneration of locus ceruleus neurons and subsequent reduction of norepinephrine concentration in locus ceruleus projection areas represent an early pathological indicator of Alzheimer's disease. In order to model the pathology of the human disease and to study the effects of norepinephrine-depletion on amyloid precursor protein processing, behaviour, and neuroinflammation, locus ceruleus degeneration was induced in mice coexpressing the swedish mutant of the amyloid precursor protein and the presenilin 1 DeltaExon 9 mutant (APP/PS1) using the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) starting treatment at 3 months of age. Norepinephrine transporter immunolabelling demonstrated severe loss of locus ceruleus neurons and loss of cortical norepinephrine transporter starting as early as 4.5 months of age and aggravating over time. Of note, dsp4-treated transgenic mice showed elevated amyloid beta levels and impaired spatial memory performance at 6.5 months of age compared to control-treated APP/PS1 transgenic mice, indicating an accelerating effect on cerebral amyloidosis and cognitive deficits. Likewise, norepinephrine-depletion increased neuroinflammation compared to transgenic controls as verified by macrophage inflammatory protein-1alpha and -1beta gene expression analysis. Exploratory activity and memory retention was compromised by age in APP/PS1 transgenic mice and further aggravated by induced noradrenergic deficiency. In contrast, novel object recognition was not influenced by norepinephrine deficiency, but by the APP/PS1 transgene at 12 months. Overall, our data indicate that early loss of noradrenergic innervation promotes amyloid deposition and modulates the activation state of inflammatory cells. This in turn could have had impact on the acceleration of cognitive deficits observed over time.
蓝斑神经元的退化和随后蓝斑投射区去甲肾上腺素浓度的降低是阿尔茨海默病的早期病理指标。为了模拟人类疾病的病理学，并研究去甲肾上腺素耗竭对淀粉样前体蛋白处理、行为和神经炎症的影响，我们使用神经毒素 N-(2-氯乙基)-N-乙基溴苯甲胺（DSP4），在 3 月龄时开始对共表达瑞典突变型淀粉样前体蛋白和早老素 1 DeltaExon 9 突变体（APP/PS1）的小鼠诱导蓝斑退化。去甲肾上腺素转运体免疫标记显示，早在 4.5 月龄时就出现严重的蓝斑神经元丢失和皮质去甲肾上腺素转运体丢失，并随着时间的推移而加重。值得注意的是，与对照处理的 APP/PS1 转基因小鼠相比，DSP4 处理的转基因小鼠在 6.5 月龄时表现出更高的淀粉样β水平和空间记忆能力受损，表明对脑淀粉样变性和认知缺陷有加速作用。同样，与转基因对照相比，去甲肾上腺素耗竭通过巨噬细胞炎症蛋白-1alpha 和 -1beta 基因表达分析增加了神经炎症。APP/PS1 转基因小鼠的探索性活动和记忆保留随着年龄的增长而受损，并因诱导的去甲肾上腺素缺乏而进一步加重。相比之下，新物体识别不受去甲肾上腺素缺乏的影响，但在 12 个月时受 APP/PS1 转基因的影响。总的来说，我们的数据表明，早期去甲肾上腺素支配的丧失促进了淀粉样蛋白的沉积，并调节了炎症细胞的激活状态。这反过来又可能对随时间推移观察到的认知缺陷的加速产生影响。
