Elsevier

Neuropharmacology

Volume 76, Part A, January 2014, Pages 9-15
Neuropharmacology

Invited review
Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies

https://doi.org/10.1016/j.neuropharm.2013.08.037Get rights and content

Highlights

  • •

    Tau filaments are encountered in a group of neurodegenerative disorders termed tauopathies.

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    Tau is an interesting disease target in its own right.

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    We review recent research on tau pathology propagation and discuss tau immunotherapy.

Abstract

Filaments made of hyperphosphorylated tau protein are encountered in a group of neurodegenerative disorders termed tauopathies. The most prevalent tauopathy, Alzheimer's disease (AD), additionally presents with extracellular deposits of the amyloid-β peptide (Aβ). Current symptomatic treatments have shown short term benefits in reducing cognitive symptoms as well as behavioral abnormalities in patients with mild to moderate AD but there is still no effective treatment to prevent or reverse AD. For decades, the amyloid cascade hypothesis of AD dominated basic research and focused pharmaceutical interest on Aβ. However, the existence of tauopathies that are devoid of Aβ deposits, together with the discovery of mutations in the tau gene leading to frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17T), confirmed the importance of tau per se in disease. Tau became an interesting disease target in its own right. We will review here recent research on cell-to-cell propagation of tau pathology, which we believe to be central to disease progression, and discuss tau immunotherapy in the light of these findings.

This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Section snippets

Tau protein

In 1975, Weingarten et al. (1975), isolated from brain a protein and named it tau for its ability to bind to microtubules. Tau is extremely heat stable and controls the polymerization of microtubules as major structural component of the axonal transport and neurotransmission machinery. In the human brain, six protein tau isoforms are derived by alternative mRNA splicing from a single gene (MAPT) located on the chromosome 17q.21.31 (Andreadis et al., 1992, Goedert et al., 1989, Neve et al., 1986

Neurodegenerative disorders with tau pathology

Pathological tau inclusions are encountered in a large number of neurodegenerative diseases grouped under the convenient term ‘tauopathies’ (Goedert et al., 2010, Spillantini et al., 1997). They include Alzheimer's disease (AD), tangle-only dementia (TD), argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick disease (PiD) as well as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), the latter being causally

Experimental transmission of tauopathy

The propagation of tau pathology during the clinical course of tauopathies points to the existence of intercellular tau aggregate transfer mechanisms. Over the past years, this notion has been experimentally substantiated through the description of cell-to-cell propagation of tau filaments, both in vivo and in vitro (Clavaguera et al., 2009, Frost et al., 2009a). In addition, in parallel to classical prion diseases, the characteristics and specifics of the different tauopathies are consistent

Immunotherapy for tauopathies

The development of therapeutic strategies to address tau pathology has until recently been restricted to small molecule approaches aimed at preventing or reversing aggregation of tau. Thus kinase inhibitors, protein phosphatase activators, deaggregating compounds and aggregation inhibitors have all been the focus of intense research activity (extensively reviewed in Lee et al. (2011)). Some compounds have advanced into clinical testing but have so far met with limited success. Only Rember®, an

Acknowledgments

This work was supported by the Swiss National Science Foundation (310030_135214) and the VELUX Foundation

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