Metaxas Athanasios, Vaitheeswaran Ramanan, Jensen Katrine T, Thygesen Camilla, Ilkjaer Laura, Darvesh Sultan, Finsen Bente
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
Curr Alzheimer Res. 2018 Mar 14;15(5):420-428. doi: 10.2174/1567205014666171004113537.
Although mood and sleep disturbances are nearly universal among patients with Alzheimer's disease (AD), brain structures involved in non-cognitive processing remain under characterized in terms of AD pathology.
This study was designed to evaluate hallmarks of AD pathology in the brainstem of the APPswe/PS1dE9 mouse model of familial AD.
Fresh-frozen sections from female, 12 month old, transgenic and control B6C3 mice (n=6/genotype) were examined for amyloid burden and neurofibrillary alterations, by using 6E10 immunohistochemistry and the Gallyas silver stain, respectively. Serotonin transporter (SERT) densities in the dorsal and the median raphe were quantified by [3H]DASB autoradiography. SERT mRNA expression was measured by RT-PCR and visualized by in situ hybridization. Neuroinflammation was evaluated by immunohistochemical staining for microglia and astrocytes, and by measuring mRNA levels of the proinflammatory cytokines TNF-α, IL-1β and IL-6.
No amyloid- and tau-associated lesions were observed in the midbrain raphe of 12 month old APPswe/PS1dE9 mice. SERT binding levels were reduced in transgenic animals compared to age-matched controls, and SERT mRNA levels were decreased by at least 50% from control values. Intense microglial, but not astrocytic immunoreactivity was observed in APPswe/PS1dE9 vs. wild-type mice. Levels of TNF-α mRNA were two-fold higher than control and correlated positively with SERT mRNA expression levels in transgenic animals.
There was no amyloid accumulation and tau-associated pathology in the midbrain raphe of 12 month old APPswe/PS1dE9 mice. However, there was a local neuroinflammatory response with loss of serotonergic markers, which may partially account for some of the behavioral symptoms of AD.
尽管情绪和睡眠障碍在阿尔茨海默病（AD）患者中几乎普遍存在，但参与非认知加工的脑结构在AD病理学方面仍未得到充分描述。
本研究旨在评估家族性AD的APPswe/PS1dE9小鼠模型脑干中AD病理学特征。
分别使用6E10免疫组织化学和Gallyas银染法，对12月龄雌性转基因和对照B6C3小鼠（每组n = 6）的新鲜冰冻切片进行淀粉样蛋白负荷和神经原纤维改变检查。通过[3H]DASB放射自显影法定量中缝背核和中缝正中核中的5-羟色胺转运体（SERT）密度。通过逆转录聚合酶链反应（RT-PCR）测量SERT mRNA表达，并通过原位杂交进行可视化。通过对小胶质细胞和星形胶质细胞进行免疫组织化学染色，以及测量促炎细胞因子TNF-α、IL-1β和IL-6的mRNA水平来评估神经炎症。
在12月龄的APPswe/PS1dE9小鼠的中缝核中未观察到淀粉样蛋白和tau相关病变。与年龄匹配的对照相比，转基因动物的SERT结合水平降低，SERT mRNA水平比对照值至少降低50%。在APPswe/PS1dE9小鼠与野生型小鼠中观察到强烈的小胶质细胞免疫反应，但未观察到星形胶质细胞免疫反应。TNF-α mRNA水平比对照高两倍，并且与转基因动物中SERT mRNA表达水平呈正相关。
在12月龄的APPswe/PS1dE9小鼠的中缝核中没有淀粉样蛋白积累和tau相关病理学改变。然而，存在局部神经炎症反应以及5-羟色胺能标记物丧失，这可能部分解释了AD的一些行为症状。
