Background:Progressive supranuclear palsy (PSP) is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with the repeated microtubule-binding domains of three (3R) or four (4R) repeats. Under normal conditions, the4R:3R ratio is 1:1. In PSP, the 4R isoform is predominantly expressed. The lesions in PSP brains are phosphorylated tau aggregates in both neurons and glial cells. These neurodegenerative diseases with abnormal tau inclusions are called tauopathies, including Alzheimer’s disease (AD). AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. Objective:Our objective was to evaluate and compare the pathological tau processing in PSP and AD. Methods:Double and triple immunofluorescence with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) were carried out and analyzed by confocal microscopy. Results:Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Truncated tau at Glu391 and Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR and the absence of intact or phosphorylated tau. Conclusion:Phosphorylated tau was abundantly evidenced in PSP as in AD. The presence of eNFTs in glial cells and neuronal bodies suggest that other truncated tau species different from those observed in AD could be present in PSP. Additional studies on truncated tau within PSP lesions could improve understanding of tau’s pathological processing and help identify a discriminatory biomarker for AD and PSP.

中文翻译：

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进行性核上性麻痹中 Tau 蛋白的分子加工：神经元和胶质细胞变性

背景：进行性核上性麻痹（PSP）是一种具有病理和临床异质性的神经退行性疾病。成人大脑中有六种 tau 亚型表达，具有三个 (3R) 或四个 (4R) 重复的微管结合域。正常情况下，4R:3R的比例为1:1。在 PSP 中，主要表达 4R 同工型。PSP 大脑中的损伤是神经元和神经胶质细胞中磷酸化的 tau 蛋白聚集。这些具有异常 tau 内含物的神经退行性疾病称为 tau 病，包括阿尔茨海默病 (AD)。AD 的特点是高度不溶性的成对螺旋丝 (PHF)，由具有异常翻译后修饰的 tau 蛋白组成。目的：我们的目的是评估和比较 PSP 和 AD 中的病理 tau 处理。方法：使用针对特定翻译后 tau 修饰（磷酸化、截短和构象变化）和噻嗪红 (TR) 的抗体进行双重和三重免疫荧光，并通过共聚焦显微镜进行分析。结果：我们的结果表明，PSP 的特征是神经原纤维缠结 (NFT) 和神经胶质细胞中磷酸化的 tau 蛋白。未观察到 Glu391 和 Asp421 处的 tau 蛋白被截断。PSP 中的细胞外 NFT (eNFT) 和神经胶质细胞表现出对 TR 的强亲和力，并且不存在完整或磷酸化的 tau。结论：与 AD 一样，磷酸化 tau 在 PSP 中也有大量证据。神经胶质细胞和神经元体中 eNFT 的存在表明，与 AD 中观察到的不同的其他截短 tau 物种也可能存在于 PSP 中。对 PSP 病变内截短 tau 蛋白的进一步研究可以提高对 tau 蛋白病理过程的理解，并有助于识别 AD 和 PSP 的区别性生物标志物。