Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau.

Sayuri Taniguchi-Watanabe,Kunimasa Arima,Shigeo Murayama,David M A Mann,Masato Hasegawa,Takeshi Iwatsubo,Haruhiko Akiyama,Tetsuaki Arai,Masami Masuda-Suzukake,Airi Tarutani,Fuyuki Kametani,Andrew Robinson,Mari Yoshida,Takashi Nonaka,Yuko Saito

doi:10.1007/s00401-015-1503-3

Abstract

Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer’s disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT. We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7–18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243–406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1503-3) contains supplementary material, which is available to authorized users.

Highlights

Tauopathies are sporadic or familial neurodegenerative diseases characterized by intracytoplasmic aggregates of hyperphosphorylated abnormal tau protein [6, 15, 23]
In accordance with previous reports, with two major bands being present at 60 and kDa in Pick bodies (PiD), two major bands at 64 and 68 kDa in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and MAPT, and three bands at 60, 64 and 68 kDa in Alzheimer’s disease (AD) were detected, confirming that the band patterns of hyperphosphorylated full-length tau are useful for biochemical diagnosis of 3R and 4R tauopathies
Immunoelectron microscopy of the sarkosyl-insoluble fractions from these tauopathy brains was performed to investigate the relationship between the trypsin-resistant cores and the morphology of the tau fibrils

Summary

Introduction

Tauopathies are sporadic or familial neurodegenerative diseases characterized by intracytoplasmic aggregates of hyperphosphorylated abnormal tau protein [6, 15, 23]. Most cases of Alzheimer’s disease (AD), and ones of frontotemporal lobar degeneration associated with tauopathy (FTLD-tau), including cases with Pick bodies (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and argyrophilic grain disease (AGD), are sporadic. The morphology and regional distribution of pathology differ among these diseases, with characteristic tau pathologies being. University, 1‐1 Yazakokarimata, Nagakute, Aichi 480‐1195, Japan They are neurofibrillary-like pathologies in cases with the M337V and R406W mutations, Pick body-like tau structures in cases with the G272V, S320F, K369I, and G389R mutations, and PSP/CBD-like glial-dominant tau pathologies in most cases with missense or intron mutations in exon10/

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