Yang Wencheng, Sopper Maggie M, Leystra-Lantz Cheryl, Strong Michael J
Robarts Research Institute, The University of Western Ontario, London, Canada.
Neurology. 2003 Dec 23;61(12):1766-73. doi: 10.1212/01.wnl.0000099372.75786.f8.
The authors compared tau protein deposition in the frontal cortex of patients with cognitive impairment of amyotrophic lateral sclerosis (ALSci) (n = 6), cognitively intact patients with ALS (n = 6), and age-matched controls (n = 6) in order to determine the pathologic substrate of ALSci.
Archival paraffin-embedded tissue was examined using Gallyas staining and immunostaining for tau-1 (phosphorylation-dependent tau epitope), tau-2 (phosphorylation independent), Alzheimer-specific tau phosphoepitopes (AT 8; ser(396) phosphorylation), beta-amyloid, glial fibrillary acid protein, SMI 31 (recognizing phosphorylated NFH), alpha-synuclein, or ubiquitin.
Tau immunoreactive astrocytic and dense neuronal inclusions were found in both ALS and ALSci, although to a greater extent in ALSci. Superficial linear spongiosis and Gallyas-positive intraneuronal aggregates, immunoreactive with tau-1 and AT 8 but rarely to ser(396) tau, were unique to ALSci. Dense extracellular aggregates were observed by both Gallyas staining and tau-1 immunostaining. Tufted degenerating astrocytes containing tau-1 and AT 8 immunoreactive aggregates and, rarely, dense Gallyas positive neuritic plaques immunoreactive with tau-1 and AT 8, but not with ser(396) tau or beta-amyloid, were observed in ALSci. Tau positive glial coiled bodies were observed in the deep cortical layers and adjacent subcortical white matter in ALSci. Although 3R and 4R tau mRNA isoforms were expressed to similar levels in the frontal cortex of all cases, the total amount of tau mRNA was increased in both ALS and ALSci. Both gray and white matter soluble tau protein expression was similar among control, ALS, and ALSci cases.
Cognitive dysfunction in ALS may reflect abnormal tau protein metabolism.
作者比较了肌萎缩侧索硬化症认知功能障碍患者（ALSci，n = 6）、认知功能正常的肌萎缩侧索硬化症患者（n = 6）以及年龄匹配的对照组（n = 6）额叶皮质中的tau蛋白沉积情况，以确定ALSci的病理基础。
使用Gallyas染色和针对tau-1（磷酸化依赖性tau表位）、tau-2（非磷酸化依赖性）、阿尔茨海默病特异性tau磷酸表位（AT 8；ser(396)磷酸化）、β-淀粉样蛋白、胶质纤维酸性蛋白、SMI 31（识别磷酸化的神经丝重链）、α-突触核蛋白或泛素的免疫染色，对存档的石蜡包埋组织进行检查。
在肌萎缩侧索硬化症（ALS）和ALSci中均发现了tau免疫反应性星形胶质细胞和致密神经元包涵体，不过在ALSci中更为常见。浅表线性海绵状变性和Gallyas阳性神经元内聚集体，与tau-1和AT 8免疫反应，但很少与ser(396) tau免疫反应，是ALSci所特有的。通过Gallyas染色和tau-1免疫染色均观察到致密的细胞外聚集体。在ALSci中观察到含有tau-1和AT 8免疫反应性聚集体的簇状变性星形胶质细胞，以及很少见的与tau-1和AT 8免疫反应，但不与ser(396) tau或β-淀粉样蛋白免疫反应的致密Gallyas阳性神经炎性斑块。在ALSci的深层皮质层和相邻的皮质下白质中观察到tau阳性胶质卷曲小体。尽管在所有病例的额叶皮质中3R和4R tau mRNA亚型的表达水平相似，但tau mRNA的总量在ALS和ALSci中均增加。在对照组、ALS和ALSci病例中，灰质和白质可溶性tau蛋白表达相似。
肌萎缩侧索硬化症中的认知功能障碍可能反映了tau蛋白代谢异常。
