Andrés-Benito P, Fernández-Dueñas V, Carmona M, Escobar L A, Torrejón-Escribano B, Aso E, Ciruela F, Ferrer I
Institut de Neuropatologia, Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, Barcelona, Spain.
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
Neuropathol Appl Neurobiol. 2017 Aug;43(5):373-392. doi: 10.1111/nan.12386. Epub 2017 Apr 19.
The present study analyses molecular characteristics of the locus coeruleus (LC) and projections to the amygdala and hippocampus at asymptomatic early and middle Braak stages of neurofibrillary tangle (NFT) pathology.
Immunohistochemistry, whole-transcriptome arrays and RT-qPCR in LC and western blotting in hippocampus and amygdala in a cohort of asymptomatic individuals at stages I-IV of NFT pathology were used.
NFTs in the LC increased in parallel with colocalized expression of tau kinases, increased neuroketal adducts and decreased superoxide dismutase 1 in neurons with hyperphosphorylated tau and decreased voltage-dependent anion channel in neurons containing truncated tau were found. These were accompanied by increased microglia and AIF1, CD68, PTGS2, IL1β, IL6 and TNF-α gene expression. Whole-transcriptome arrays revealed upregulation of genes coding for proteins associated with heat shock protein binding and genes associated with ATP metabolism and downregulation of genes coding for DNA-binding proteins and members of the small nucleolar RNAs family, at stage IV when compared with stage I. Tyrosine hydroxylase (TH) immunoreactivity was preserved in neurons of the LC, but decreased TH and increased α adrenergic receptor protein levels were found in the hippocampus and the amygdala.
Complex alteration of several metabolic pathways occurs in the LC accompanying NFT formation at early and middle asymptomatic stages of NFT pathology. Dopaminergic/noradrenergic denervation and increased expression of α adrenergic receptor in the hippocampus and amygdala occur at first stage of NFT pathology, suggesting compensatory activation in the face of decreased adrenergic input occurring before clinical evidence of cognitive impairment and depression.
本研究分析了在神经纤维缠结（NFT）病理的无症状早期和中期Braak阶段蓝斑（LC）的分子特征以及向杏仁核和海马体的投射。
对一组处于NFT病理I-IV期的无症状个体，使用LC中的免疫组织化学、全转录组阵列和RT-qPCR以及海马体和杏仁核中的蛋白质印迹法。
发现LC中的NFTs与tau激酶的共定位表达平行增加，神经酮加合物增加，tau过度磷酸化的神经元中超氧化物歧化酶1减少，含有截短tau的神经元中电压依赖性阴离子通道减少。这些伴随着小胶质细胞增加以及AIF1、CD68、PTGS2、IL1β、IL6和TNF-α基因表达增加。与I期相比，IV期的全转录组阵列显示编码与热休克蛋白结合相关蛋白质的基因以及与ATP代谢相关的基因上调，而编码DNA结合蛋白和小核仁RNA家族成员的基因下调。酪氨酸羟化酶（TH）免疫反应性在LC的神经元中得以保留，但在海马体和杏仁核中发现TH减少且α肾上腺素能受体蛋白水平增加。
在NFT病理的早期和中期无症状阶段，LC中伴随着NFT形成出现了几种代谢途径的复杂改变。在NFT病理的第一阶段，海马体和杏仁核中出现多巴胺能/去甲肾上腺素能神经支配缺失以及α肾上腺素能受体表达增加，这表明在认知障碍和抑郁的临床证据出现之前，面对肾上腺素能输入减少时存在代偿性激活。
