Date Published: December 19, 2017
Publisher: BioMed Central
Author(s): Amrit Mudher, Morvane Colin, Simon Dujardin, Miguel Medina, Ilse Dewachter, Seyedeh Maryam Alavi Naini, Eva-Maria Mandelkow, Eckhard Mandelkow, Luc Buée, Michel Goedert, Jean-Pierre Brion.
Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a “prion-like” mechanism involving transfer of abnormal tau seeds from a “donor cell” to a “recipient cell” and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a “prion-like” mechanism and proposes a number of recommendations for directing future research. Recommendations for definitions of frequently used terms in the tau field are presented in an attempt to clarify and standardize interpretation of research findings. Molecular and cellular factors affecting tau aggregation are briefly reviewed, as are potential contributions of physiological and pathological post-translational modifications of tau. Additionally, the experimental evidence for tau seeding and “prion-like” propagation of tau aggregation that has emerged from cellular assays and in vivo models is discussed. Propagation of tau pathology using “prion-like” mechanisms is expected to incorporate several steps including cellular uptake, templated seeding, secretion and intercellular transfer through synaptic and non-synaptic pathways. The experimental findings supporting each of these steps are reviewed. The clinical validity of these experimental findings is then debated by considering the supportive or contradictory findings from patient samples. Further, the role of physiological tau release in this scenario is examined because emerging data shows that tau is secreted but the physiological function (if any) of this secretion in the context of propagation of pathological tau seeds is unclear. Bona fide prions exhibit specific properties, including transmission from cell to cell, tissue to tissue and organism to organism. The propagation of tau pathology has so far not been shown to exhibit all of these steps and how this influences the debate of whether or not abnormal tau species can propagate in a “prion-like” manner is discussed. The exact nature of tau seeds responsible for propagation of tau pathology in human tauopathies remains controversial; it might be tightly linked to the existence of tau strains stably propagating peculiar patterns of neuropathological lesions, corresponding to the different patterns seen in human tauopathies. That this is a property shared by all seed-competent tau conformers is not yet firmly established. Further investigation is also required to clarify the relationship between propagation of tau aggregates and tau-induced toxicity. Genetic variants identified as risks factors for tauopathies might play a role in propagation of tau pathology, but many more studies are needed to document this. The contribution of selective vulnerability of neuronal populations, as an alternative to prion-like mechanisms to explain spreading of tau pathology needs to be clarified. Learning from the prion field will be helpful to enhance our understanding of propagation of tau pathology. Finally, development of better models is expected to answer some of these key questions and allow for the testing of propagation-centred therapies.
The sequential appearance of tau pathology in the brains of Tauopathy patients has traditionally been considered to arise due to differential vulnerability of susceptible brain regions to disease processes, which is then reflected in the stereotypical progression of lesions throughout the brain. Recent evidence challenges this view and promotes the idea that tau pathology spreads through the brain using a prion-like mechanism. During the first EUROTAU meeting (Lille, France, April 2017 (http://lucbuee.fr/crbst_10.html), a round table discussion critically appraised this evidence and reflected on its clinical relevance. This review summarises that debate and makes recommendations that were suggested for clarification and identification of key-points for future studies. Additionally it was noted that various terms are used to describe tau pathology and that this can lead to confusion. Defining these terms would clarify their meaning and therefore standardise their use in future publications.
There are numerous terms that are commonly used to describe aspects of tau pathology. These are listed and defined in Table 1 together with recommendations for consistent usage in future publications.Table 1Terminology for main tau assemblies and definition criteriaNameDefinitionStructural criteriaMolecular criteriaTau pathologyBroad term designing abnormal molecular changes of normal tau as well as morphological changes.Mislocalization of tau and/or pathological tau assembly in inclusion or aggregate.Post-translational modifications of tau. Tau insolubility.Tau inclusionMorphologically distinct subcellular structure inside a cell.Microscopically visible structure. Made of tau aggregates.Properties of tau aggregates.Tau aggregateAssembly of tau into oligomers, fibrils, filaments, and NFTMolecular tau assembly based on highly ordered ß-sheet structure.Positive with ß-sheet (amyloid) sensitive dyes (Thioflavine T, Congo Red, LCOs). Tau hyperphosphorylationTau seedA tau species inducing aggregation of tauMolecular tau assemblies of various size providing a templatePositive with ß-sheet sensitive dyesLiquid coacervates of tauMembraneless organelles in a state of Liquid-liquid phase separationCoacervation of tau into liquid dropletsCan acquire ß-sheet structure.TanglesNeuronal tau inclusions in somataComposed of bundles of PHFs and SFs. Gallyas and Campbell-Switzer positive.3R and 4R tau positive in ADNeuropil threadsTau inclusions in nerve cell dendritesComposed of bundles of PHFs and SFs. Gallyas and Campbell-Switzer positive.3R and 4R tau positive in ADDystrophic neuritesAxons forming the neuritic corona of plaquesNerve cell processes in contact with Aß deposits. Some of them contain PHFs and SFs and are Gallyas and Campbell-Switzer positive.3R and 4R tau positive in ADArgyrophilic grainsNeuronal granular tau inclusions in dendritesTau filaments. Gallyas positive. Campbell-Switzer negative.4R tau positive in AGDPick bodiesSpherical tau inclusions in nerve cell somataFilamentous and vesicular material. Gallyas-negative. Campbell-Switzer positive.3R tau positive in Pick disease.Oligodendroglial coiled bodiesTau inclusions in cell bodies of oligodendrocytesPHF/SF like filaments. Gallyas positive. Campbell-Switzer negative.4R tau positive in PSP and CBDGlobular oligodendroglial inclusionsGlobular oligodendroglial tau inclusionGallyas positive.Mainly 4R tau positive in GGTsTufted astrocytesAstrocytes with thin and long radial processes containing tau inclusionsTau filaments in cytoplasm and proximal portions of astrocytic processes. Gallyas positive. Campbell-Switzer negative.4R tau positive in PSPAstrocytic plaquesAstrocytes containing tau inclusions in a corona-like arrangmentTau filaments in distal portions of astrocytic processes. Gallyas positive. Campbell-Switzer negative.4R tau positive in CBDThorn-shaped astrocytesAstrocytes with thorn-shaped processes containing tau inclusionsSpine-like perinuclear tau filaments. Gallyas positive.4R tau positive in ARTAGAD Alzheimer’s disease, AGD Argyrophilic grain disease, ARTAG, Ageing-related tau astrogliopathy, CBD Corticobasal degeneration, GGTs Globular glial tauopathies, PSP Progressive supranuclear palsy, LCOs Luminescent conjugated oligothiophenesEach of the various tau inclusions is positive with some LCOsA common feature of all tau assemblies is their immunoreactivity with tau antibodies, although peculiar tau epitopes can distinguish between them. For more details on specific tau inclusions, tauopathies, and silver staining properties see [9, 54, 86, 131]
The concept that brain spreading of tau pathology in tauopathy occurs by a “prion-like” mechanism is fast gaining popularity. The key tenets of this hypothesis are that diverse conformational tau strains exist in different tauopathies, and that they drive templated aggregation followed by the intercellular propagation of tau pathology. While the evidence in favour of this hypothesis is growing daily, its clinical relevance is still debated . Furthermore, it is not clear how spread of tau pathology through this “prion-like propagation” relates to spread of pathology arising from differential spatio-temporal vulnerability of connected neuronal populations. Future studies which take into account some of the points raised here are needed to document the respective roles of these pathological mechanisms in tauopathies. Nonetheless, since clinical symptoms are likely to manifest only after extensive spread of pathology, understanding all potential modes employable by pathological tau to traverse neural circuits opens novel therapeutic avenues to arrest the spread of tau aggregates at a preclinical stage.