Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead.

Petr Novak,Norbert Zilka,Eva Kontsekova,Michal Novak

doi:10.3389/fnins.2018.00798

Abstract

Neurofibrillary pathology comprised of pathological tau protein is closely tied to a range of neurodegenerative disorders, the most common of which is Alzheimer’s disease. While they are individually rarer, a range of other disorders, the tauopathies (including Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, primary progressive aphasia, and ∼50% of behavioral variant frontotemporal dementia cases) display pronounced underlying tau pathology. In all cases, the distribution and amount of tau pathology closely correlates with the severity and phenotype of cognitive impairment, and with the pattern and degree of brain atrophy. Successfully counteracting tau pathology is likely to halt or slow the progression of these debilitating disorders. This makes tau a target of prime importance, yet an elusive one. The diversity of the tau proteome and post-translational modifications, as well as pathophysiology of tau are reviewed. Beginning 2013, a range of tau-targeted immunotherapies have entered clinical development; these therapies, and their common themes and differences are reviewed. The manuscript provides an extensive discussion on epitope selection for immunotherapies against tau pathology, on immunological mechanisms involved in their action, and challenges such as immune senescence, vaccine design, or evolution of epitopes. Furthermore, we provide methodological recommendations for the characterization of active vaccines and antibodies, animal models, and the target itself – the diseased tau proteome.

Highlights

Reviewed by: Naruhiko Sahara, National Institute of Radiological Sciences (NIRS), Japan Katharina Schindowski Zimmermann, Biberach University of Applied Sciences, Germany
The results of preclinical animal studies of the immunotherapies in Table 4 showed that the animal model of choice was treated with the compound, whereupon its tau pathology was reduced, and clinical symptoms improved
All tau-targeted immunotherapies in clinical trials are at early stages of development

Summary

Introduction

We provide methodological recommendations for the characterization of active vaccines and antibodies, animal models, and the target itself – the diseased tau proteome In his seminal discovery, Alois Alzheimer has described two prominent changes in the brain of his patient – senile plaques composed of amyloid-β, and neurofibrillary pathology composed of protein tau (Alzheimer, 1907; Braak et al, 1994). Alois Alzheimer has described two prominent changes in the brain of his patient – senile plaques composed of amyloid-β, and neurofibrillary pathology composed of protein tau (Alzheimer, 1907; Braak et al, 1994) The former received massive attention due to the simple fact that rare monogenic mutations in the amyloid precursor protein, or in the presenilins involved in its processing cause a neurodegenerative phenotype that is indistinguishable from ‘sporadic’ AD that makes up >95% of AD cases (Blennow et al, 2006).

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Results

Conclusion