PDF(Pubmed)
Abstract：
The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer\'s disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick\'s disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick\'s disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.
摘要：
最常见的神经变性蛋白质病包括在脑中具有错误折叠的tau或α-突触核蛋白沉积的疾病。PNS中的病理蛋白聚集体在α-突触核蛋白病中得到了广泛认可，并且最近作为诊断生物标志物引起了关注。然而,Tau蛋白病的观察很少。为了表征PNS在tau蛋白病变中的参与，我们调查了54例tau病变[进行性核上性麻痹（PSP），n=15；阿尔茨海默病（AD），n=18；慢性创伤性脑病（CTE），n=5；和皮质基底变性（CBD），n=6；皮克病，n=9；边缘占优势的神经元包涵体4-重复tau蛋白病（LNT），n=1]使用免疫组织化学，Gallyas银染,生物化学,和接种试验。大多数PSP病例显示PNS中磷酸化和4次重复tau免疫反应性tau沉积如下：（tau阳性病例数/可用病例数）颅神经III：7/8（88％）；IX/X：10/11（91％）；和XII：6/6（100％）；脊髓前根：10/10（100％）。PSP中的tau阳性内含物通常在轴突中显示出具有原纤维（神经原纤维缠结样）形态的结构，这些结构也被Gallyas银染色识别。CBD病例很少显示细颗粒状非嗜银tau沉积物。相比之下,PNS中的tau病理在AD中不明显，CTE和Pick病病例。单个LNT病例在PNS中也显示tau病理。在PSP中,PNS-tau受累的严重程度与相应细胞核的严重程度相关，虽然,偶尔,p-tau沉积物存在于颅神经中，但不存在于相关的脑干核中。毫不奇怪,大多数PSP病例表现为眼球运动障碍和延髓症状，一些病例还显示了运动神经元的下位征。使用tau生物传感器细胞，我们首次证明了tau在PNS中的播种能力。总之,突出的PNS-tau将PSP与其他tau蛋白病区分开来。PSP和CBD之间PNS-tau的形态学差异表明PNS中的tau病理可以反映中枢神经系统中的tau病理。PSP中tau病变的高频率和早期存在表明PNS-tau可能具有临床和生物标志物相关性。
