- Letter to the Editor
- Open Access
EuroTau: towing scientists to tau without tautology
© The Author(s). 2017
- Received: 7 November 2017
- Accepted: 7 November 2017
- Published: 29 November 2017
What a change in situation... A few years ago, at the height of the amyloid cascade, tau biologists, (so called Tauists) were virtually invisible in Alzheimer’s disease conferences, which were occupied by amyloid biologists (so called baptists). Currently, sessions dedicated to tau and Tauopathies are increasing in several congresses on neurodegenerative diseases, including AAIC and AD/PD. Interest in tau biology is so great that a Tau consortium, set up especially to provide a forum for this area of research, has been created in the US. In Europe, tau biologists have gathered in tau-focused meetings organized in Cambridge, UK (2010, 2012), Madrid, Spain (2013) and more recently in Lille, France (2017). The microtubule-associated tau protein is not a new protein, it was discovered in 1975, and has featured in the game of neurodegenerative disorders since 1985. Tau is now the “Figura”, and the renewed interest in this protein leads one to ask “Why such interest in tau proteins and why now?”.
There are many reasons for this burgeoning interest. Firstly the fact that most amyloid-centred therapies for Alzheimer’s disease (AD) and related disorders have demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. While drug development efforts in the last two decades have primarily focused on the amyloid cascade hypothesis, with disappointing results so far, tau-based strategies have, until recently, received little attention. This is despite the presence of extensive tau pathology, which is central not just to AD but is a key component of several other neurodegenerative diseases collectively called “Tauopathies”. Thus, focusing on tau as a drug target can have a profound bearing on disease-modification for several neurodegenerative conditions facing our ageing society today.
Secondly, multiple facets of tau biology, and therefore manifold potential implications for its role in Tauopathies, have emerged recently. Several laboratories world-wide made the seminal discovery that tau is the main component of the neurofibrillary tangles (NFT) found in AD patients more than thirty years ago, but since then, evidence has accumulated showing that posttranslational modifications such as acetylation, glycosylation, phosphorylation and truncation, among others [10, 14, 18] are pivotal in regulating tau functions.
Thirdly, the discovery of some families with highly penetrant, dominant mutations within the tau gene causing fronto-temporal lobar degeneration  demonstrated that tau dysfunction, including its alternative splicing is sufficient to cause neurodegeneration and clinical dementia [1, 8, 14, 15]. Whilst it is still not clear how the mutations in the tau gene cause neurodegeneration, the overall effect of these mutations is predicted to be an increase in the rate of tau aggregation and eventually the formation of insoluble tau inclusions.
As a result of this growing interest in tau biology, new hypotheses on the physiological and pathological role of tau are growing. It is no longer believed to be simply a microtubule-associated protein (MAP)  with recent advances in our understanding of tau’s cellular functions revealing functions beyond its classical role as a MAP. This has provided novel insights into its causative role in neurodegeneration. Such functions include neuronal polarization, axonogenesis, interactions with the plasma membrane and scaffold proteins, signal transduction, cell cycle, DNA/RNA protection, determination of dendritic spine density, and regulation of normal synaptic function [4, 11, 17]. Some of these are actively being pursued at present , thus broadening our range of potential therapeutic tools to treat AD and other tauopathies. Collectively, the recognition of tau as a key player in the pathobiology of human neurodegenerative diseases has driven substantial efforts to understand its biological and pathological functions.
The spread of tau pathology through the brain of tauopathy patients has been the subject of recent research because of the appearance of Aβ deposits and tau aggregates in the human brain as a function of age suggest that tau inclusions appear earlier than amyloid β plaques [2, 6]. Tau aggregates in the locus coeruleus are seen in young individuals and the typical AD associated tau pathology manifests in the entorhinal cortex from where it spreads to other brain regions.This differential distribution underlies the Braak staging for tau pathology in AD , but similar stereotypical spatiotemporal spreading of tau inclusions has also been described in other tauopathies such as argyrophilic grain disease . Traditionally, this spatio-temporal spread of tau pathology through brain regions was believed to occur in a cell autonomous manner with the spread being determined by differential susceptibility of tissues affected. Numerous reports now challenge this view and suggest that tau pathology propagates from cell to cell and this underpins its spread through anatomically connected brain regions [3, 5]. Furthermore, evidence is emerging that these tau aggregates can adopt distinct conformations or ‘strains’ with remarkable differences in their structural and phenotypic traits . This idea has been denoted the “prion-like” hypothesis and it predicts transmissibility and seeding mechanisms of many amyloidogenic proteins including tau. This idea describes spread of tau pathology but does not necessarily explain spread of neurodegeneration because it is not yet clear how and if the two are related in Tauopathies. Moreoever, there is of course the possibility that, some tau assemblies in specific conformations may not be toxic, and may in fact be inert or even neuro-protective. The relationship between tau conformation within tau assemblies, its toxicity and role in propagation of pathology are still unclear and the subject of intensive research. Nonetheless, these protein assemblies represent targets for therapeutic strategies and potential biomarkers [10, 14–16, 18].
“What is the evidence that the spread of tau pathology occurs via a prion-like mechanism?” chaired by Amrit Mudher and Jean-Pierre Brion.
“Atypical tau functions” chaired by Ioannis Sotiropoulos and Marie-Christine Galas.
The aim of the round table discussions was to reflect on the current state of affairs in these key areas of tau Biology and to make recommendations for future studies. The report of the third round table is also available . Additionally, a talk given by Prof. Maria Spillantini entitled: “Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions” was selected for publication as part of this series.
Stay tune and join us at EuroTau 2018 in Lille, France.
EuroTau has been funded by French academic funds and charities/foundations (Fondation Plan Alzheimer, LabEx DISTALZ, LiCEND Centre of Excellence, SFR DN2M - University of Lille). We would also like to acknowledge Valérie Buée-Scherrer, Sophie Halliez, Laetitia Coudert and the “Alzheimer & Tauopathies” team for logistics of the first EuroTau meeting and the Lille Learning Centre Innovation (https://lilliad.univ-lille.fr/) for welcoming us.
All authors defined the structure and ideas of this manuscript. LB and AM wrote the manuscript. JPB, JA, and MM discussed the first draft of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Andreadis A (2012) Tau splicing and the intricacies of dementia. J Cell Physiol 227(3):1220–1225View ArticlePubMedPubMed CentralGoogle Scholar
- Braak H, Del Tredici K (2011) The pathological process underlying AD in individuals under thirty. Acta Neuropathol 121(2):171–181View ArticlePubMedGoogle Scholar
- Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11(7):909–913View ArticlePubMedPubMed CentralGoogle Scholar
- Dawson HN, Ferreira A, Eyster MV et al (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau-deficient mice. J Cell Sci 114(6):1179–1187PubMedGoogle Scholar
- de Calignon A, Polydoro M, Suarez-Calvet M et al (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73(4):685–697View ArticlePubMedPubMed CentralGoogle Scholar
- Duyckaerts C, Braak H, Brion JP et al (2015) PART is part of Alzheimer disease. Acta Neuropathol 129(5):749–756View ArticlePubMedPubMed CentralGoogle Scholar
- Gozes I, Höglinger G, Quinn JP, Hooper NM, Höglund K (2017) Tau diagnostics and clinical studies. J Mol Neurosci 63(2):123–30Google Scholar
- Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393(6686):702–705View ArticlePubMedGoogle Scholar
- Kaufman SK, Thomas TL, Del Tredici K, Braak H, Diamond MI (2017) Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue. Acta Neuropathol Commun 5(1):41. https://doi.org/10.1186/s40478-017-0442-8 View ArticlePubMedPubMed CentralGoogle Scholar
- Medina M, Avila J (2014) New perspectives on the role of tau in Alzheimer’s disease. Implications for therapy. Biochem Pharmacol 88(4):540–547View ArticlePubMedGoogle Scholar
- Merino-Serrais P, Benavides-Piccione R, Blazquez-Llorca L et al (2013) The influence of phospho-τ on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease. Brain 136(6):1913–1928View ArticlePubMedPubMed CentralGoogle Scholar
- Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of tau. Neuron 70(3):410–426View ArticlePubMedPubMed CentralGoogle Scholar
- Saito Y, Ruberu NN, Sawabe M et al (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63(9):911–918View ArticlePubMedGoogle Scholar
- Šimić G, Babić Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, Bažadona D, Buée L, de Silva R, Di Giovanni G, Wischik C, Hof PR (2016) Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomol Ther 6(1):6. https://doi.org/10.3390/biom6010006 Google Scholar
- Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12(6):609–622View ArticlePubMedGoogle Scholar
- Tosun D, Landau S, Aisen PS, Petersen RC, Mintun M, Jagust W, Weiner MW, Initiative A’s DN (2017) Association between tau deposition and antecedent amyloid-β accumulation rates in normal and early symptomatic individuals. Brain 140(5):1499–1512View ArticlePubMedGoogle Scholar
- Violet M, Delattre L, Tardivel M, Sultan A, Chauderlier A, Caillierez R, Talahari S, Nesslany F, Lefebvre B, Bonnefoy E, Buée L, Galas MC (2014) A major role for tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci 8:84View ArticlePubMedPubMed CentralGoogle Scholar
- Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17(1):5–21View ArticlePubMedGoogle Scholar