Departamento de Fisiología Biofísica y Neurociencias, CINVESTAV, México City, México.
Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, México.
J Alzheimers Dis. 2021;79(4):1517-1531. doi: 10.3233/JAD-201139.
Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells.
Our objective was to evaluate and compare the processing of pathological tau in PSP and AD.
Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy.
Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau.
Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP.
阿尔茨海默病（AD）和进行性核上性麻痹（PSP）是神经退行性疾病的例子，其特征是异常的 tau 包含物，这些疾病被称为 tau 病。AD 的特征是由具有异常翻译后修饰的 tau 组成的高度不溶性配对螺旋丝（PHF）。PSP 是一种具有病理和临床异质性的神经退行性疾病。成人脑中表达六种 tau 同工型，具有三个（3R）或四个（4R）重复的重复微管结合结构域。在 AD 中，4R:3R 比值为 1:1。在 PSP 中，4R 同工型占优势。PSP 大脑中的病变包含神经元和神经胶质细胞中磷酸化的 tau 聚集物。
我们的目的是评估和比较 PSP 和 AD 中病理性 tau 的处理。
使用针对特定翻译后 tau 修饰（磷酸化、截断和构象变化）和噻嗪红（TR）染色的抗体进行双重和三重免疫荧光标记，并通过共聚焦显微镜进行分析。
我们的结果表明，PSP 的特征是神经原纤维缠结（NFTs）和神经胶质细胞中的磷酸化 tau。未观察到 Glu391 或 Asp421 截断的 tau。PSP 中的细胞外 NFT（eNFT）和神经胶质细胞在没有完整或磷酸化 tau 的情况下对 TR 表现出强烈的亲和力。
PSP 中磷酸化 tau 的丰度与 AD 中相同。来自神经胶质细胞和神经元体的 eNFT 的发展表明，可能存在与 AD 中观察到的不同的截断 tau 物种。对 PSP 病变中截断 tau 的进一步研究可以增进我们对 tau 病理处理的理解，并有助于确定 AD 和 PSP 的鉴别生物标志物。
