Sonia Do Carmo
Maria Grazia Spillantini
A. Claudio Cuello- 1Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
- 2Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge, United Kingdom
- 3Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- 4Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
- 5Department of Pharmacology, Oxford University, Oxford, United Kingdom
Editorial on the Research Topic
Tau Pathology in Neurological Disorders
The histological alterations now known as neurofibrillary tangles (NFTs) were first described in 1906 by Alois Alzheimer using light microscopy and silver staining (1); in the late 1960's it was shown by electron microscopy that they were made of paired helical filaments (PHFs) and a small percentage of straight filaments (SFs) (2, 3). Around this time, it was also shown that abundant NFTs were associated with cognitive decline (4, 5). Between 1985 and 1991 it was shown by immunohistochemistry, biochemical approaches and molecular cloning that PHFs and SFs are made of hyperphosphorylated tau protein (6–11) a microtubule-associated protein first described in 1975 (12). Tau filaments from Alzheimer's disease were shown to be made of a structured core and the less structured fuzzy coat (10, 13, 14). These pioneering accomplishments paved the way to further recognize the complexity of tau translation and splicing leading to the identification of the different tau isoforms in the healthy brain and modification such as phosphorylation, truncation and conformational changes in neurodegenerative diseases (7, 15–18). In normal human brain, six tau isoforms are expressed from a single gene by alternative mRNA splicing (19, 20). They differ by the presence or absence of two amino-terminal inserts and an extra repeat of 31 amino acids in the C-terminal region. Depending on its presence, one can divide tau isoforms into two groups, three isoforms with three repeats and three isoforms with four repeats. Both groups of isoforms are expressed at similar levels in normal brain. The repeats and some adjoining sequences make up the microtubule-binding region of tau. They also form part of the filament core, suggesting that physiological function and pathological assembly are mutually incompatible. In Alzheimer's disease, all six tau isoforms are present in PHFs and SFs (15). Electron microscopy and image reconstruction showed that tau filaments from Alzheimer's disease are made of two identical C-shaped protofilaments (21). However, the resolution was insufficient to see individual amino acids. This changed in 2017, when the structure of the Alzheimer tau fold was obtained at near-atomic resolution using electron cryo-microscopy (cryo-EM) (22). The same tau fold has been described in multiple individuals with Alzheimer's disease (23), as well as in some cases with prion protein amyloidosis (24) and in primary age-related tauopathy (PART) (25). Different tau folds have been described in Pick's disease (23), chronic traumatic encephalopathy (26), and corticobasal degeneration (27).
These findings tell us that Alzheimer NFTs are made of filamentous tau, but they do not say anything about the relevance of tau assembly for the disease process. This required human genetics. In June 1998, three publications reported mutations in MAPT, the tau gene, in familial forms of frontotemporal dementia (28–30). Even though MAPT mutations do not cause Alzheimer's disease, these findings proved that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. To date, 65 missense, deletion and intronic mutations in MAPT have been shown to cause disease. Gene dosage mutations have also been reported (31). Importantly, filamentous tau assemblies were present in all cases. Depending on the mutations, assemblies are made of either 3R, 4R, or 3R+4R tau. Similar findings have been described for idiopathic human tauopathies. Thus, Pick's disease is a 3R tauopathy, whereas progressive supranuclear palsy, globular glial tauopathy, corticobasal degeneration, and argyrophilic grain disease are 4R tauopathies. Alzheimer's disease, familial British dementia, familial Danish dementia, chronic traumatic encephalopathy and Guam-Parkinsonism-Dementia are 3R+4R tauopathies.
In 2009, it was shown that assembled tau exhibits prion-like properties in experimental systems (32, 33). It is now well-established that a tau seed can induce the assembly of monomeric protein, but it remains to be established what role the prion-like spreading of assembled tau plays in human brain. Although the staging of tau pathology is associated with development of dementia (34–37) and is consistent with prion-like spreading, it cannot prove its existence. Perhaps the best evidence for prion-like spreading in human brain comes from a study showing the absence of assembled tau in denervated frontal cortex from Alzheimer's disease (38). Using sucrose gradient fractionation of the brains from mice transgenic for human mutant P301S tau and a cellular assay, it has been shown that small tau filaments are the most potent seeds (39). It remains to be determined which species of assembled tau cause neurodegeneration. It has been suggested that tau oligomers may play an important role (40–42). Current knowledge also suggests that the intercellular transfer of tau aggregates is dependent on the tau species (43) and is likely mediated through mechanisms such as the release of tau seeds into the extracellular space in a free form or within vesicles, such as exosomes, which enter recipient neighboring cells by fluid-phase or receptor-mediated endocytosis or by vesicle fusion. The transfer of tau seeds to recipient cells can also occur through nanotubes [reviewed in (44)]. The recipient cells can be either neurons or other brain cell types such as microglia, astrocytes, oligodendrocytes and endothelial cells as highlighted in this Research Topic.
Notwithstanding that the presence and importance of tau and its modifications in neuropathology were first studied in Alzheimer's disease, tau inclusions are also represented in other neurodegenerative diseases grouped under the umbrella term “tauopathies.” The strong association between NFTs and cognitive capabilities in the continuum of Alzheimer's disease, and observed also in Down syndrome, was described in a wealth of literature (34, 45–57). These observations were also corroborated by the recent report of an autosomal dominant Alzheimer's disease case who presented mild cognitive impairment at the age of 70, 3 decades later of what expected in the family and who presented with extreme amyloid burden but minimal tau pathology (58). In addition to Alzheimer's disease, tau pathology has been described in other neurodegenerative diseases which lack significant Aβ pathology including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and parkinsonism linked to chromosome 17, among others (30, 59–62) [reviewed in (63, 64)]. In consequence the term “tauopathy” used to describe the pathology in a family with MAPT mutation (61) encompassing now all the above neurodegenerative diseases.
Still, despite the colossal amount of knowledge on tau biology gathered so far, significant questions related to how tau transitions from the homeostatic into the disease state remain at least partially unanswered: (1) How do the differential levels of tau post-translational modifications and aggregation affect tau propagation and its biological activity? (2) What is the contribution of tau regions outside the microtubule binding domain to tau physiology and pathology? (3) Which factors define the phenotypic heterogeneity of tauopathies; is miRNA-mediated regulation of tau involved? (4) What are the functional consequences of tau interaction with cellular organelles such as the nucleus and mitochondria? (5) How and how much does the transmission of tau to non-neuronal cells contribute to tauopathy progression and what is the functional consequence of such transmission in the recipient cells? (6) What is the contribution of tau pathology to the malfunction of the brain vasculature and neurovascular unit in Alzheimer's disease? (7) To which extent does tau intersect with other pathologies to drive neurodegeneration and cognitive dysfunction? (8) How does the current knowledge of tau biology translate into tau-targeted therapies, and can these be of benefit in tauopathies other than Alzheimer's?
We present this Research Topic and e-book to provide an insight into some of these questions and highlights the most recent advances in understanding the molecular and cellular mechanisms underlying the evolution of tau pathology in Alzheimer's disease and in other tauopathies.
In this Research Topic, the extent of tau post-translational modifications, the assembly states and conformations of tau, the distribution of tau in different cell types, the spreading of tau to cells and tissues and the toxic effects of abnormal tau are comprehensively reviewed by Kang et al. who conclude that “although heterogeneity [of tau biology] in the here and now is an inconvenient truth, embracing this effect, defining its origins and then adjusting approaches may pave the way for more sophisticated testing and more realistic interventions.”
The extent of tau post-translational modifications across tauopathies, their frequency, and their effect on tau function, aggregation and degradation are further reviewed by Alquezar et al. It is noteworthy that the vast number of sites on the tau protein that can be targeted by specific modifications, often on the same amino acid residue, opens the door for a competition between post-translational modifications that defines a dynamic code regulating tau function, aggregation and degradation and could therefore explain the heterogeneity of tauopathies. The significance of tau phosphorylation is further emphasized by Duquette et al. who discuss that the pattern of tau hyperphosphorylation varies greatly in physiological and pathological conditions. Tau hyperphosphorylation appears mainly protective and reversible in brain development and in hibernating animals. However, in pathological conditions the pattern of tau hyperphosphorylation is disease-specific in the same way as the atomic structure of their intrinsic tau filaments as revealed by cryo-EM.
The disease-specificity of tau phosphorylation is further highlighted in amyotrophic lateral sclerosis (ALS) and in ALS frontotemporal spectrum disorder (ALS-FTSD) as reviewed by Strong et al. where the distinctive pathological phosphorylation at Thr175 promotes exposure of the phosphatase activating domain in the tau N-terminus thereby activating GSK3β-mediated phosphorylation at Thr231 leading to the formation of tau oligomers. Indeed, it has been shown that tau phosphorylation and aggregation are intimately linked and tau hyperphosphorylation by proline-directed stress kinases, such as GSK3β favors tau oligomerization (65). Novel information regarding the reason for which oligomeric tau might be more neurotoxic than fibrillar tau is provided by Jiang et al. Using a seeding assay in primary neuron cultures expressing human 4R0N tau Jiang et al. demonstrate that oligomeric seeds of tau show a greater co-localization with RNA binding proteins associated with stress granules, an element that could contribute to increased pathology.
The molecular organization of the tau protein in relation to the functional interactions of diverse tau regions, including the particular features of the tau non-microtubule binding region are eloquently reviewed by Brandt et al. Of relevance, tau knockout in mouse models results in a several of effects, with only some of them related to microtubule-dependent processes. This highlights the role of the N-terminal region of tau in the organization and function of membrane organelles, such as the plasma membrane (66, 67) and synaptic vesicles as well as its involvement in tauopathies.
Tau aggregates are mostly found within neurons where they disrupt synaptic plasticity, cell signaling, and DNA integrity eventually leading to cell death. Indeed, stress and pathological conditions promote tau accumulation in cellular compartments other than axons which are considered their main sub-cellular localisation. As such, tau can also be found in the soma, the dendrites, and the nucleus where it can interact with nuclear components. As reviewed by Diez and Wegmann, the dual localisation of tau in cytoplasm and nucleus suggests the transport of tau between the two compartments by mechanisms still to be defined given the absence of nuclear localisation signals. The nuclear tau interaction with DNA appears to be regulated by its phosphorylation and it has been suggested as protective of double stranded DNA breaks and participant of regulation of gene expression.
Such nuclear localization may also promote chromosome stability. On the other hand, cytoplasmic tau could alter the structure of the nuclear envelope and promote the aggregation of nucleoporins in the cytoplasm. This would alter the nucleocytoplasmic protein transport and therefore impacting major cellular signaling pathways. In response to stress nuclear tau can also translocate to the nucleolus and be found in stress granules in the cytoplasm as revealed in ALS and ALS-FTSD and discussed by Strong et al. Moreover, tau pathology impacts negatively adult hippocampal neurogenesis in both Alzheimer's disease and tau mouse models as summarized by Houben et al. This provides a new insight on a less documented tau-related pathological pathway leading to cognitive deficits. However, the studies carried so far have produced conflicting results.
The presence of tau aggregates is being increasingly reported in non-neuronal brain cells. Whether such aggregates derive directly from the intracellular microtubule tau detachment of glial expressed tau or from the glial uptake of neuronal tau is still a matter of debate (68–70). It is well-established that astrocytes play a critical role in supporting neuronal function and that pathological astrocytic changes are associated with and precede neuronal loss in Alzheimer's disease and overt tau aggregation in mouse models of tau aggregation (71). Interestingly, while tau deposition in astrocytes is mostly seen in aging, it can also be found in tauopathies, although with varying frequency according with the disease condition, as reviewed by Reid et al. This deposition of tau impacts the function of astrocytes through mechanisms which includes disruption of calcium signaling, gliotransmitters release, and immune responses consequentially affecting neuronal function. In addition, astrocytes may participate in the spreading of tau via the astrocytic water channel aquaporin-4 (AQP4) involved in the elimination of aberrant proteins.
The disruption of astrocytic and microglial function by tau may also participate in vascular dysfunction, an early characteristic of Alzheimer's disease (72). Canepa and Fossati discuss studies in vitro, in animal and human supporting the view that tau has deleterious effects on cellular and molecular pathways in vascular and immune cells which lead to the dysregulation of the neurovascular unit. These authors also propose mechanisms mediating the effects of tau on the cerebrovasculature, including tau-induced mitochondrial dysfunction which would lead to increased reactive oxygen species and decreased ATP production and caspase activation. Further to it, Bryant et al. provide novel data showing that microvessels isolated from the dorsolateral prefrontal cortex of Alzheimer's subjects display extensive tau pathology (Braak V/VI, B3) and a strong upregulation of endothelial senescence and leukocyte adhesion-related genes.
The disease-specificity of tau accumulation in glia and the role of oligodendrocytes in tau spreading is further highlighted by Zareba-Paslawska et al. Using a humanized tau mouse line overexpressing all six human tau isoforms in a murine tau knockout background inoculated with insoluble tau extracts from corticobasal degeneration brain homogenates, they show a 4R-tau dependent spreading primarily mediated by oligodendrocytes.
Given the critical role of tau in Alzheimer's and other tauopathies, understanding how tau expression, splicing, post-translational modifications and aggregation are regulated is essential. Boscher et al. describe the involvement of microRNAs (miRNAs) in such regulation. In particular, loss of the miR-132/212 cluster is strongly associated with memory decline and increased tau pathology. Intriguingly, Boscher et al. show that deletion of the miR-132/212 in PS19 mice, a model of tauopathy, had little effects on disease phenotypes with divergent effects on tau biology. They also discuss potential pitfalls explaining these observations including the lack of adequate tools and animal models to study the involvement of miRNAs in tau pathology.
As evidenced in this Research Topic, because of its key function and its dysregulation and aggregation in Alzheimer's and other tauopathies, tau has become an attractive target for therapy. Existing tau-targeting approaches, their advantages and limitations were elegantly summarized by Masnata et al., with an emphasis on their potential in treating Huntington's disease, a secondary tauopathy. Some approaches target tau phosphorylation using kinase inhibitors, phosphatase activators or immunotherapy targeted at tau phosphorylation at sites that are either hyperphosphorylated or exclusively phosphorylated in Alzheimer's. In the particular case of immunotherapy, a few factors must be considered when designing antibodies including the differential toxicity of tau seeds and the disease-specificity of tau hyperphosphorylation, which precludes the use of immunotherapy targets across tauopathies as discussed by Duquette et al.
The disease-specific characteristics of tau aggregates across tauopathies as revealed by cryo-EM, their trans-cellular propagation and the information gathered from models used to study tau aggregation further prompted the development of approaches targeting tau self-assembly as discussed by Oakley et al. and by Masnata et al. The present most promising avenues include tau aggregation inhibitors, and active or passive immunisation against either post-translational modifications facilitating tau aggregation and conformationally altered forms of tau or aggregated tau, thus preventing the formation of PHFs.
Tau spreading could also be targeted by inhibiting tau receptors favouring spreading. A recent study by Rauch et al. (73) showed that neuronal surface low-density-lipoprotein-receptor-related protein-1 (LRP1) mediates internalization and spreading of both physiological tau and pathogenic tau oligomers, suggesting that LRP1 could be a suitable target for intervention. Through their commentary on the paper by Rauch et al., Fearon and Lynch highlight the potential and limitations of LRP1 as a key player in tau physiology and its potential as a therapeutic target for tauopathies. As previously suggested in Fearon and Lynch's the in vitro and animal data do not always translate to human studies.
Other approaches to mitigate the deleterious effects of pathological tau are being examined such as modulating MAPT gene expression. As revealed in preclinical studies, the restoration of physiological miRNA levels could also provide an attractive alternative.
As emphasized in several contributions to this Research Topic, models mimicking tau biology in physiological and pathological conditions, while allowing testing potential therapeutics they present considerable limitations. To overcome these limitations Shamir et al. introduce a neuron-like in vitro model of human origin which shows the expected toxicity of human-derived PHF-enriched tau and enables studies on the internalization and interaction of tau antibodies with pathological tau.
A significant limitation of mouse tauopathy models is that while mouse models provide invaluable insight into tau biology and pathology, they do not recapitulate the human tau splicing into six isoforms and the human 3R/4R ratio [reviewed in (74, 75)]. There are a few mouse models which mimic human tau pathology leading to brain atrophy such as the PS19 and the P301S tau (76, 77). More recently, P301S tau transgenic mice with targeted replacement of endogenous ApoE with human ApoE revealed the important role of ApoE in regulating tau-mediated neurodegeneration. In this model, the expression of the human ApoE4 protein caused the most severe tauopathy leading to human-like brain atrophy (78). In this regard rat models of tauopathy display significant advantages (74). For example, the McGill-R962-hTau rat model of tauopathy, as similar models under development, overexpresses the longest isoform of human tau (2N4R) with the P301S mutation causative of FTDP-17 under the control of the CaMKII alpha gene promoter. These rats progressively develop human-like tau pathology and related phenotype with tau hyperphosphorylation and conformationally-altered tau, resulting in NFT-like inclusions and neuroinflammation followed by neuronal loss, marked by brain atrophy, ventricular dilation, demyelination, and cognitive impairment (79). Of relevance to the study of the human-like tauopathy and therapeutics rats are genetically and physiologically closer to humans than mice and unlike mice they display all six human tau isoforms, although not at the same ratio. Furthermore, the rat endogenous ApoE protein has a high homology with the human ApoE4 protein.
Conclusion
This collection of reviews covers a wide variety of progresses regarding the participation of the tau protein in a diversity of neurodegenerative conditions. These contributions bring new ideas regarding physiological and pathological molecular mechanisms involving this multi-faceted microtubule-associated protein. These contributions offer an excellent background to further define the differential pathological aspects of diverse tauopathies. It supports the analysis of tau-mediated glia-neuron interactions and their impact in the homeostatic maintenance of the brain vascular bed. The main future challenge in the field will remain the development of effective therapeutics able to halt or delay the devastating consequences of brain tau pathology. This e-book should be of much assistance to conceive and investigate novel therapeutic approaches of eventual clinical value.
Author Contributions
SD, MS, and AC have participated in writing the Editorial and approved it for publication. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Alzheimer A. Über einen eigenartigen schweren ErkrankungsprozeB der Hirnrinde. Neurologisches Centralblatt. (1906) 23:1129–36.
2. KIDD M. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature. (1963) 197:192–3. doi: 10.1038/197192b0
3. Hirano A, Dembitzer HM, Kurland LT, Zimmerman HM. The fine structure of some intraganglionic alterations. Neurofibrillary tangles, granulovacuolar bodies and “rod-like” structures as seen in Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. J Neuropathol Exp Neurol. (1968) 27:167–82. doi: 10.1097/00005072-196804000-00001
4. Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. (1968) 114:797–811. doi: 10.1192/bjp.114.512.797
5. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci. (1970) 11:205–42. doi: 10.1016/0022-510X(70)90063-8
6. Brion JP, Passareiro H, Nunez J, Flament-Durand J. Mise en évidence immunologique de la protéine tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d'Alzheimer. Arch Biol. (1985) 95:229–35.
7. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA. (1986) 83:4913–7. doi: 10.1073/pnas.83.13.4913
8. Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA. (1986) 83:4044–8. doi: 10.1073/pnas.83.11.4044
9. Wood JG, Mirra SS, Pollock NJ, Binder LI. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci USA. (1986) 83:4040–3. doi: 10.1073/pnas.83.11.4040
10. Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA. (1988) 85:4051–5. doi: 10.1073/pnas.85.11.4051
11. Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. (1991) 251:675–8. doi: 10.1126/science.1899488
12. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA. (1975) 72:1858–62. doi: 10.1073/pnas.72.5.1858
13. Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA. (1988) 85:4884–8. doi: 10.1073/pnas.85.13.4884
14. Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA. (1988) 85:4506–10. doi: 10.1073/pnas.85.12.4506
15. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. (1992) 8:159–68. doi: 10.1016/0896-6273(92)90117-V
16. Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem. (1986) 99:1807–10. doi: 10.1093/oxfordjournals.jbchem.a135662
17. Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, et al. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. (2006) 580:3582–8. doi: 10.1016/j.febslet.2006.05.029
18. Weaver CL, Espinoza M, Kress Y, Davies P. Conformational change as one of the earliest alterations of tau in Alzheimer's disease. Neurobiol Aging. (2000) 21:719–27. doi: 10.1016/S0197-4580(00)00157-3
19. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. (1989) 3:519–26. doi: 10.1016/0896-6273(89)90210-9
20. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. (1989) 8:393–9. doi: 10.1002/j.1460-2075.1989.tb03390.x
21. Crowther RA. Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci USA. (1991) 88:2288–92. doi: 10.1073/pnas.88.6.2288
22. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, et al. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. (2017) 547:185–90. doi: 10.1038/nature23002
23. Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, et al. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. (2018) 561:137–40. doi: 10.1038/s41586-018-0454-y
24. Hallinan GI, Hoq MR, Ghosh M, Vago FS, Fernandez A, Garringer HJ, et al. Structure of Tau filaments in Prion protein amyloidoses. Acta Neuropathol. (2021) 142:227–41. doi: 10.1007/s00401-021-02336-w
25. Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, et al. Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. Acta Neuropathol. (2021) 141:697–708. doi: 10.1007/s00401-021-02294-3
26. Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R, et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. (2019) 568:420–3. doi: 10.1038/s41586-019-1026-5
27. Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B, et al. Novel tau filament fold in corticobasal degeneration. Nature. (2020) 580:283–7. doi: 10.1038/s41586-020-2043-0
28. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. (1998) 43:815–25. doi: 10.1002/ana.410430617
29. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. (1998) 393:702–5. doi: 10.1038/31508
30. Spillantini MG, Crowther RA, Kamphorst W, Heutink P, van Swieten JC. Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. (1998) 153:1359–63. doi: 10.1016/S0002-9440(10)65721-5
31. Wallon D, Boluda S, Rovelet-Lecrux A, Thierry M, Lagarde J, Miguel L, et al. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers. Acta Neuropathol. (2021) 142:259–78. doi: 10.1007/s00401-021-02320-4
32. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. (2009) 284:12845–52. doi: 10.1074/jbc.M808759200
33. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. (2009) 11:909–13. doi: 10.1038/ncb1901
34. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (1991) 82:239–59. doi: 10.1007/BF00308809
35. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex. (1991) 1:103–16. doi: 10.1093/cercor/1.1.103
36. Mena R, Wischik CM, Novak M, Milstein C, Cuello AC. A progressive deposition of paired helical filaments (PHF) in the brain characterizes the evolution of dementia in Alzheimer's disease. An immunocytochemical study with a monoclonal antibody against the PHF core. J Neuropathol Exp Neurol. (1991) 50:474–90. doi: 10.1097/00005072-199107000-00008
37. Duyckaerts C, Bennecib M, Grignon Y, Uchihara T, He Y, Piette F, et al. Modeling the relation between neurofibrillary tangles and intellectual status. Neurobiol Aging. (1997) 18:267–73. doi: 10.1016/S0197-4580(97)80306-5
38. Duyckaerts C, Uchihara T, Seilhean D, He Y, Hauw JJ. Dissociation of Alzheimer type pathology in a disconnected piece of cortex. Acta Neuropathol. (1997) 93:501–7. doi: 10.1007/s004010050645
39. Jackson SJ, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella CV, et al. Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J Neurosci. (2016) 36:762–72. doi: 10.1523/JNEUROSCI.3542-15.2016
40. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Clos AL, Jackson GR, Kayed R. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener. (2011) 6:39. doi: 10.1186/1750-1326-6-39
41. Fá M, Puzzo D, Piacentini R, Staniszewski A, Zhang H, Baltrons MA, et al. Extracellular tau oligomers produce an immediate impairment of LTP and memory. Sci Rep. (2016) 6:19393. doi: 10.1038/srep19393
42. Shafiei SS, Guerrero-Muñoz MJ, Castillo-Carranza DL. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front Aging Neurosci. (2017) 9:83. doi: 10.3389/fnagi.2017.00083
43. Dujardin S, Bégard S, Caillierez R, Lachaud C, Carrier S, Lieger S, et al. Different tau species lead to heterogeneous tau pathology propagation and misfolding. Acta Neuropathol Commun. (2018) 6:132. doi: 10.1186/s40478-018-0637-7
44. Goedert M, Eisenberg DS, Crowther RA. Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci. (2017) 40:189–210. doi: 10.1146/annurev-neuro-072116-031153
45. Haroutunian V, Purohit DP, Perl DP, Marin D, Khan K, Lantz M, et al. Neurofibrillary tangles in non-demented elderly subjects and mild Alzheimer disease. Arch Neurol. (1999) 56:713–8. doi: 10.1001/archneur.56.6.713
46. Nelson PT, Jicha GA, Schmitt FA, Liu H, Davis DG, Mendiondo MS, et al. Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol. (2007) 66:1136–46. doi: 10.1097/nen.0b013e31815c5efb
47. Robinson JL, Geser F, Corrada MM, Berlau DJ, Arnold SE, Lee VM, et al. Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old. Brain. (2011) 134:3708–15. doi: 10.1093/brain/awr308
48. Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. (2004) 61:378–84. doi: 10.1001/archneur.61.3.378
49. Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. J Am Med Assoc Neurol. (2019) 76:915–24. doi: 10.1001/jamaneurol.2019.1424
50. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. (1992) 42:631–9. doi: 10.1212/WNL.42.3.631
51. Ghoshal N, García-Sierra F, Wuu J, Leurgans S, Bennett DA, Berry RW, et al. Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer's disease. Exp Neurol. (2002) 177:475–93. doi: 10.1006/exnr.2002.8014
52. Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA, et al. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. Brain. (2015) 138:1370–81. doi: 10.1093/brain/awv050
53. Guillozet AL, Weintraub S, Mash DC, Mesulam MM. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol. (2003) 60:729–36. doi: 10.1001/archneur.60.5.729
54. Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology. (2003) 60:1495–500. doi: 10.1212/01.WNL.0000063311.58879.01
55. Digma LA, Madsen JR, Reas ET, Dale AM, Brewer JB, Banks SJ. Alzheimer's disease neuroimaging initiative. Tau and atrophy: domain-specific relationships with cognition. Alzheimers Res Ther. (2019) 11:65. doi: 10.1186/s13195-019-0518-8
56. Gordon BA, Blazey TM, Christensen J, Dincer A, Flores S, Keefe S, et al. Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers. Brain. (2019) 142:1063–76. doi: 10.1093/brain/awz019
57. Rafii MS, Lukic AS, Andrews RD, Brewer J, Rissman RA, Strother SC, et al. Down syndrome biomarker initiative and the Alzheimer's disease neuroimaging initiative. PET imaging of tau pathology and relationship to amyloid, longitudinal MRI, and cognitive change in down syndrome: results from the down syndrome biomarker initiative (DSBI). J Alzheimers Dis. (2017) 60:439–50. doi: 10.3233/JAD-170390
58. Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. (2019) 25:1680–3. doi: 10.1038/s41591-019-0611-3
59. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol. (1998) 8:387–402. doi: 10.1111/j.1750-3639.1998.tb00162.x
60. Spillantini MG, Crowther RA, Goedert M. Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles. Acta Neuropathol. (1996) 92:42–8. doi: 10.1007/s004010050487
61. Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci USA. (1997) 94:4113–8. doi: 10.1073/pnas.94.8.4113
62. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA. (1998) 95:7737–41. doi: 10.1073/pnas.95.13.7737
63. Goedert M, Spillantini MG. Ordered assembly of tau protein and neurodegeneration. Adv Exp Med Biol. (2019) 1184:3–21. doi: 10.1007/978-981-32-9358-8_1
64. Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull. (2016) 126:238–92. doi: 10.1016/j.brainresbull.2016.08.018
65. Nuebling GS, Plesch E, Ruf VC, Högen T, Lorenzl S, Kamp F, et al. Binding of metal-ion-induced tau oligomers to lipid surfaces is enhanced by GSK-3β-mediated phosphorylation. ACS Chem Neurosci. (2020) 11:880–7. doi: 10.1021/acschemneuro.9b00459
66. Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J Cell Biol. (1995) 131:1327–40. doi: 10.1083/jcb.131.5.1327
67. Pooler AM, Hanger DP. Functional implications of the association of tau with the plasma membrane. Biochem Soc Trans. (2010) 38:1012–5. doi: 10.1042/BST0381012
68. Brelstaff J, Tolkovsky AM, Ghetti B, Goedert M, Spillantini MG. Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep. (2018) 24:1939–48.e4. doi: 10.1016/j.celrep.2018.07.072
69. Hallmann AL, Araúzo-Bravo MJ, Mavrommatis L, Ehrlich M, Röpke A, Brockhaus J, et al. Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein. Sci Rep. (2017) 7:42991. doi: 10.1038/srep42991
70. Walker LC. Glial tauopathy: neurons optional? J Exp Med. (2020) 217:e20191915. doi: 10.1084/jem.20191915
71. Sidoryk-Wegrzynowicz M, Gerber YN, Ries M, Sastre M, Tolkovsky AM, Spillantini MG. Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions. Acta Neuropathol Commun. (2017) 5:89. doi: 10.1186/s40478-017-0478-9
72. Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC. Alzheimer's disease neuroimaging initiative. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun. (2016) 7:11934. doi: 10.1038/ncomms11934
73. Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, et al. LRP1 is a master regulator of tau uptake and spread. Nature. (2020) 580:381–5. doi: 10.1038/s41586-020-2156-5
74. Do Carmo S, Cuello AC. Modeling Alzheimer's disease in transgenic rats. Mol Neurodegener. (2013) 8:37. doi: 10.1186/1750-1326-8-37
75. Jankowsky JL, Zheng H. Practical considerations for choosing a mouse model of Alzheimer's disease. Mol Neurodegener. (2017) 12:89. doi: 10.1186/s13024-017-0231-7
76. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. (2007) 53:337–51. doi: 10.1016/j.neuron.2007.01.010
77. Hampton DW, Webber DJ, Bilican B, Goedert M, Spillantini MG, Chandran S. Cell-mediated neuroprotection in a mouse model of human tauopathy. J Neurosci. (2010) 30:9973–83. doi: 10.1523/JNEUROSCI.0834-10.2010
78. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. (2017) 549:523–7. doi: 10.1038/nature24016
Keywords: tau pathology, tauopathies, Alzheimer's disease, neurodegeneration, dementia, tau therapeutics
Citation: Do Carmo S, Spillantini MG and Cuello AC (2021) Editorial: Tau Pathology in Neurological Disorders. Front. Neurol. 12:754669. doi: 10.3389/fneur.2021.754669
Received: 06 August 2021; Accepted: 26 August 2021;
Published: 24 September 2021.
Edited and reviewed by: Bruce Miller, University of California, San Francisco, United States
Copyright © 2021 Do Carmo, Spillantini and Cuello. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: A. Claudio Cuello, Y2xhdWRpby5jdWVsbG8mI3gwMDA0MDttY2dpbGwuY2E=