Szot Patricia, Van Dam Debby, White Sylvia S, Franklin Allyn, Staufenbiel Matthias, De Deyn Peter Paul
Northwest Network for Mental Illness Research, Education, and Clinical Center, Veterans Administration Puget Sound Health Care System, and Department of Psychiatry and Behavioral Science, University of Washington, Seattle 98195, USA.
Neurosci Lett. 2009 Sep 29;463(1):93-7. doi: 10.1016/j.neulet.2009.07.055. Epub 2009 Jul 23.
Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by the loss of neurons in specific regions of the CNS including the locus coeruleus (LC), the major noradrenergic locus in the CNS. Several animal models of AD have been developed that exhibit some of the pathophysiological changes in the CNS that are observed in AD patients. The purpose of this study was to determine if the integrity of the LC noradrenergic system is altered in the amyloid precursor protein 23 (APP23) mouse model of AD at the age of 3, 6 and 12 months through quantification of tyrosine hydroxylase (TH) mRNA expression. Despite a previous study suggesting alterations in the noradrenergic transmission system of APP23 mice, the current study failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic neurons of APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate an age-dependent effect on TH mRNA expression. Both the number of TH-containing neurons and the amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months with no difference between 6 and 12 months. These observations indicate that any study comparing the noradrenergic system between WT (C57Bl/6) and experimental mice must strictly choose the age to be tested and limit age differences between control and experimental groups to the absolute minimum. More importantly, when long-term therapeutic interventions targeting the noradrenergic system are applied to mouse models, and related parameters are studied longitudinally, care should be taken to distinguish between potential therapeutic and strain-specific developmental or age-related alterations.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是中枢神经系统（CNS）特定区域的神经元丧失，包括蓝斑（LC），它是中枢神经系统中主要的去甲肾上腺素能位点。已经开发了几种AD动物模型，这些模型表现出AD患者中枢神经系统中观察到的一些病理生理变化。本研究的目的是通过定量酪氨酸羟化酶（TH）mRNA表达，确定在3、6和12月龄的淀粉样前体蛋白23（APP23）AD小鼠模型中，LC去甲肾上腺素能系统的完整性是否发生改变。尽管先前有研究表明APP23小鼠的去甲肾上腺素能传递系统存在改变，但本研究未能显示APP23小鼠与野生型（WT）同窝仔鼠相比，TH阳性神经元数量或LC去甲肾上腺素能神经元中的表达有变化。然而，本研究确实证明了年龄对TH mRNA表达有影响。含TH的神经元数量和TH阳性颗粒/神经元数量在3至6月龄之间显著增加，6至12月龄之间无差异。这些观察结果表明，任何比较WT（C57Bl/6）和实验小鼠去甲肾上腺素能系统的研究都必须严格选择测试年龄，并将对照组和实验组之间的年龄差异限制到绝对最小值。更重要的是，当将针对去甲肾上腺素能系统的长期治疗干预应用于小鼠模型并纵向研究相关参数时，应注意区分潜在的治疗效果和品系特异性发育或年龄相关的改变。
