Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Müllerstrasse 178, 13342 Berlin, Germany.
Neuroscience. 2011 Mar 10;176:396-407. doi: 10.1016/j.neuroscience.2010.11.052. Epub 2010 Dec 1.
Degeneration of locus ceruleus (LC) neurons and subsequent reduction of norepinephrine (NE) in LC projection areas represent an early pathological indicator of Alzheimer's disease (AD). In order to study the effects of NE depletion on cortical and hippocampal adrenergic system changes, LC degeneration was induced in 3-month-old APP/PS1 mice by the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4). Dsp4 induced a widespread loss of norepinephrine transporter binding in multiple brain structures already at 4.5 months. This was accompanied by changes of α-1-, α-2-, and β-1-adreneroceptor binding sites as well as altered adrenoceptor mRNA expression. In parallel, we observed increased micro- and astrogliosis in cortical and hippocampal structures in dsp4-treated groups. In addition, the expression of the pro-inflammatory cytokines CCL2 and IL-1β were induced in both, dsp4-treated and APP/PS1-transgenic mice, whereas IL-1α was only up-regulated in dsp4-treated APP/PS1 mice. Concerning amyloid β (Aβ) deposition, we observed an elevation of Aβ1-42 levels in aged dsp4-treated APP/PS1 mice. These data support the hypothesis that LC degeneration leads to dysregulation of adrenergic receptors and exacerbation of Aβ-induced neuroinflammation, both of which are exploitable for early disease marker development.
蓝斑（LC）神经元的退化以及随后 LC 投射区去甲肾上腺素（NE）的减少，是阿尔茨海默病（AD）的早期病理指标。为了研究 NE 耗竭对皮质和海马肾上腺素能系统变化的影响，通过神经毒素 N-（2-氯乙基）-N-乙基溴苯甲胺（DSP4）诱导 3 月龄 APP/PS1 小鼠的 LC 退化。DSP4 在 4.5 个月时已在多个脑结构中引起广泛的去甲肾上腺素转运体结合丧失。这伴随着 α-1-、α-2-和 β-1-肾上腺素能受体结合位点的变化以及改变的肾上腺素能受体 mRNA 表达。平行地，我们观察到在 DSP4 处理组的皮质和海马结构中微胶质和星形胶质细胞增生增加。此外，促炎细胞因子 CCL2 和 IL-1β在 DSP4 处理和 APP/PS1 转基因小鼠中均被诱导表达，而 IL-1α仅在 DSP4 处理的 APP/PS1 小鼠中上调。关于淀粉样蛋白β（Aβ）沉积，我们观察到在年老的 DSP4 处理的 APP/PS1 小鼠中 Aβ1-42 水平升高。这些数据支持这样的假设，即 LC 退化导致肾上腺素能受体的失调和 Aβ 诱导的神经炎症加剧，这两者都可用于早期疾病标志物的开发。
