Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration

Alejandra Martínez-Maldonado, Miguel Ángel Ontiveros-Torres, Charles R. Harrington, José Francisco Montiel-Sosa, Raúl García-Tapia Prandiz, Patricia Bocanegra-López, Andrew Michael Sorsby-Vargas, Marely Bravo-Muñoz, Benjamín Florán-Garduño, Ignacio Villanueva-Fierro, George Perry, Linda Garcés-Ramírez, Fidel De La Cruz-López, Sandra Martínez-Robles, Mar Pacheco-Herrero, José Luna-Muñoz* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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. Objective: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. Methods: 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. Results: 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. Conclusion: 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.
Original languageEnglish
Pages (from-to)1517-1531
Number of pages15
JournalJournal of Alzheimer's Disease
Volume79
Issue number4
Early online date15 Jan 2021
DOIs
Publication statusPublished - 16 Feb 2021

Keywords

  • Alzheimer’s disease
  • neurofibrillary tangle
  • progressive supranuclear palsy
  • tau protein
  • truncation

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