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Tau and neurodegenerative disease: the story so far

Key Points

  • Tau pathology, consisting of hyperphosphorylated tau, is a hallmark of Alzheimer disease (AD) and other tauopathies

  • Hyperphosphorylation converts tau from a normal functional protein to a neurotoxic protein, and induces prion-like templating activity

  • Protein phosphatase 2A has key roles in multiple aetiopathogenic mechanisms of sporadic AD

  • Inhibition of hyperphosphorylation and clearance of the pathological tau are promising therapeutic approaches for the tauopathies; in addition, neuroregeneration can rescue both tau pathology and cognitive impairment

  • A phase I clinical trial of an active tau immunization vaccine was recently completed in patients with AD

  • Assays for tau levels in cerebrospinal fluid and plasma are available, and tau radiotracers for PET are under development

Abstract

In 1975, tau protein was isolated as a microtubule-associated factor from the porcine brain. In the previous year, a paired helical filament (PHF) protein had been identified in neurofibrillary tangles in the brains of individuals with Alzheimer disease (AD), but it was not until 1986 that the PHF protein and tau were discovered to be one and the same. In the AD brain, tau was found to be abnormally hyperphosphorylated, and it inhibited rather than promoted in vitro microtubule assembly. Almost 80 disease-causing exonic missense and intronic silent mutations in the tau gene have been found in familial cases of frontotemporal dementia but, to date, no such mutation has been found in AD. The first phase I clinical trial of an active tau immunization vaccine in patients with AD was recently completed. Assays for tau levels in cerebrospinal fluid and plasma are now available, and tau radiotracers for PET are under development. In this article, we provide an overview of the pivotal discoveries in the tau research field over the past 40 years. We also review the current status of the field, including disease mechanisms and therapeutic approaches.

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Figure 1: Timeline of discoveries and advances in the tau research field.
Figure 2: Tau mutations and alternative splicing of the MAPT pre-mRNA in FTD.
Figure 3: Tau as a primary and secondary cause of disease.
Figure 4: Generation of tau seeds and spread of tau pathology.
Figure 5: Key steps in AD neurofibrillary degeneration, and possible therapeutic approaches.

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Acknowledgements

We are most grateful to Ezzat El-Akkad for his help in preparation of figures, and to Janet Murphy for secretarial assistance. For seminal discoveries and advances, input was sought from several leaders in the field, including Jesús Avila, Michel Goedert, Maria Spillantini, Eva Maria Mandelkow, Eckhard Mandelkow, Jürgen Götz, Michal Novak, Virginia M. Lee, John Trojanowski, Luc Buee, Akihiko Takashima and Kenneth Kosik. K.I., F.L. and C.-X.G. work for the New York State Office for People with Developmental Disabilities (NYS OPWDD).

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Khalid Iqbal.

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K.I. serves on the scientific advisory board of AXON Neuroscience, has received research grants from Ever NeuroPharma and Signum Biosciences, and holds several patents on treatment of Alzheimer disease and related conditions. C.-X.G. serves on the scientific advisory board of Alectos Therapeutics. F.L. declares no competing interests.

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Iqbal, K., Liu, F. & Gong, CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12, 15–27 (2016). https://doi.org/10.1038/nrneurol.2015.225

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