Novel monoclonal antibodies targeting the microtubule-binding domain of human tau.

Hemant K. Paudel,Cara L Croft,Benoit I Giasson,Yong Ran,Brenda D Moore,Paramita Chakrabarty,Yona Levites,Todd E Golde

doi:10.1371/journal.pone.0195211

Abstract

Tauopathies including Alzheimer’s disease and Progressive Supranuclear Palsy are a diverse group of progressive neurodegenerative disorders pathologically defined by inclusions containing aberrantly aggregated, post-translationally modified tau. The tau pathology burden correlates with neurodegeneration and dementia observed in these diseases. The microtubule binding domain of tau is essential for its physiological functions in promoting neuronal cytoskeletal stability, however it is also required for tau to assemble into an amyloid structure that comprises pathological inclusions. A series of novel monoclonal antibodies were generated which recognize the second and fourth microtubule-binding repeat domain of tau, thus enabling the identification specifically of 4-repeat tau versus 3-/4-repeat tau, respectively. These antibodies are highly specific for tau and recognize pathological tau inclusions in human tauopathies including Alzheimer’s disease and Progressive Supranuclear Palsy and in transgenic mouse models of tauopathies. These new antibodies will be useful for identifying and characterizing different tauopathies and as tools to target tau pathology in these diseases.

Highlights

Tauopathies are a group of neurodegenerative diseases predominantly identifiable by inclusions composed of aggregated, highly phosphorylated and cleaved microtubule (MT)-associated protein tau (MAPT) [1]
Generation of antibodies targeting the microtubule binding domain of tau Mice were immunized with the synthetic peptides corresponding to the MT binding domain (MTBD) in 4R human tau 244–372 (K18) conjugated to 21–140 αS at the N-terminus or 21–140 αS at the N-terminus plus Aβ1–42 at the C-terminus
This selectivity for tau was confirmed by detection of tau pathology by immunohistochemistry of human Alzheimer’s disease (AD) post-mortem brain tissue with abundant tau pathology

Summary

Introduction

Tauopathies are a group of neurodegenerative diseases predominantly identifiable by inclusions composed of aggregated, highly phosphorylated and cleaved microtubule (MT)-associated protein tau (MAPT) [1]. This burden of tau inclusion pathology has been shown to correlate with the cognitive decline observed in these diseases, as well as, neurodegeneration [2,3,4]. Cognitive decline associates more with the tau burden compared to the amyloid-β load in Alzheimer’s disease (AD) [5]. Tauopathies are pathologically and symptomatically heterogeneous and include AD, Progressive Supranuclear Palsy (PSP), corticobasal degeneration (CBD), Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [1, 6]. Tau exists as six different isoforms, ranging from 352 to 441 amino acids in length as a result of alternative splicing of exons 2, 3 and 10 [7,8,9] and is natively unfolded [10].

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