Mechanisms of secretion and spreading of pathological tau protein
Open accessAbstract
Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer’s disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.
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CSF p-tau biomarkers likely indicate an active process of tau secretion, and one that is correlated with cerebral Aβ deposition in early disease.
“Thus, it is suggested that CSF p-tau biomarkers likely indicate an active process of tau secretion, and one that is correlated with cerebral Aβ deposition in early disease.20, 21, 22”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [22]
The Cell-to-cell transfer of tau section says CSF in AD contains elevated phosphorylated tau and that active cellular processes contribute to tau secretion. The paper also discusses amyloid pathology as a possible trigger for tau release, but it does not state that CSF p-tau biomarkers correlate with cerebral Aβ deposition in early disease. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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Near-atomic model of microtubule-tau interactions
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“Of particular importance are also two cysteine residues located in R2 and R3, which form disulfide bridges during tau dimerization and which have been found to constitute a critical step in the formation of tau fibrils [44].”
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Alzheimer's DiseasePreprint
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“In line with these results, Arendt and colleagues suggested that hyperphosphorylation of tau may have a physiological role, possibly related to synaptic plasticity [73].”
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“Interestingly, other disease-associated proteins, such as α-synuclein and Aβ, also have the ability to form bacteriotoxin-like annular protofibrils and pore-like structures in membranes [183, 184], suggesting that this mechanism could play a central role in unconventional secretion of several misfolded aggregating pro…”
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Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity
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BackgroundHuman Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
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Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer's disease
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Microtubule-associated protein tau is essential for long-term depression in the hippocampus
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Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
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The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease
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Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo
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Template-assisted filament growth by parallel stacking of tau
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Loss of Bin1 Promotes the Propagation of Tau Pathology
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“Tau is indeed capable of rupturing the endosome membrane [200, 201], although the molecular mechanisms of this process, or which forms of tau mediate it, have not been fully elucidated.”
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Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation
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“However, the formation of tunneling nanotubes—or cellular contacts in other forms—is not required for cell-to-cell transfer of tau oligomers and aggregates, as several studies have shown that tau pathology can be transferred from one cell to another via the extracellular medium without cell-to-cell contacts or presenc…”
BackgroundInfluentialLiquid–liquid phase separation of tau protein: The crucial role of electrostatic interactions
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Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins
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TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading
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Unconventional Secretion Mediates the Trans-cellular Spreading of Tau
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Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro
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Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments.
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Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo
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“1 3 known tauopathy characterized by inclusions of 3R-tau is Pick’s disease [89].”
BackgroundPotential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease
Roh, J. H., Jiang, H., Finn, M. B., Stewart, F. R., Mahan, T. E., Cirrito, J. R., Heda, A., Snider, B. J., Li, M., Yanagisawa, M., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20141788 · Cited by 230 · see citing works
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Constitutive secretion of tau protein by an unconventional mechanism
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CSF biomarkers predict a more malignant outcome in Alzheimer disease
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Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia
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Ectosomes: A New Mechanism for Non-Exosomal Secretion of Tau Protein
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“In this study, microglia internalized neuronally secreted tau from the extracellular space and packed it in exosomes—which appear to contain the most toxic forms of tau [127, 155].”
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Dural lymphatics regulate clearance of extracellular tau from the CNS
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Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs)
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Alzheimer-like Changes in Microtubule-associated Protein Tau Induced by Sulfated Glycosaminoglycans
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“Several studies suggest that while a fraction of the total extracellular tau is indeed found in exosomes or ectosomes, a large fraction of the extracellular tau pool exists in vesicle-free form [149, 155, 157, 158] (Table 2).”
BackgroundRetarded Axonal Transport of R406W Mutant Tau in Transgenic Mice with a Neurodegenerative Tauopathy
Zhang, B., Higuchi, M., Yoshiyama, Y., Ishihara, T., Forman, M. S., Martinez, D., Joyce, S. C., Trojanowski, J. Q., & Lee, V. M. ‐. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0797-04.2004 · Cited by 187 · see citing works
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“In line with this, a recent study demonstrated that different tau species can be internalized by different cellular mechanisms [195].”
ResultDetection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles
Guix, F. X., Corbett, G. T., Cha, D., Mustapić, M., Liu, W., Mengel, D., Chen, Z., Aïkawa, E., Young‐Pearse, T. L., Kapogiannis, D., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030663 · Cited by 182 · see citing works
Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons
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Tau protein and tau aggregation inhibitors
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Differential Assembly of Human Tau Isoforms in the Presence of Arachidonic Acid
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Extracellular Tau Levels Are Influenced by Variability in Tau That Is Associated with Tauopathies
Karch, C. M. M., Jeng, A. T., & Goate, A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.380642 · Cited by 171 · see citing works
Caspase-cleaved Tau Expression Induces Mitochondrial Dysfunction in Immortalized Cortical Neurons
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Secretion of Tau via an Unconventional Non-vesicular Mechanism
Merezhko, M., Brunello, C. A., Yan, X., Vihinen, H., Jokitalo, E., Uronen, R., & Huttunen, H. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.078 · Cited by 170 · see citing works
Self-citationALZHEIMER'S DISEASE: PAIRED HELICAL FILAMENTS AND CYTOMEMBRANES
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CSF biomarkers predict rate of cognitive decline in Alzheimer disease
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Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles
Simón, D., García‐García, E., Royo, F., Falcón‐Pérez, J. M., & Ávila, J. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.11.022 · Cited by 156 · see citing works
Tau Enhances α-Synuclein Aggregation and Toxicity in Cellular Models of Synucleinopathy
Badiola, N., de Oliveira, R. M., Herrera, F., Guardia‐Laguarta, C., Gonçalves, S. A., Pera, M., Suárez‐Calvet, M., Clarimón, J., Outeiro, T. F., & Lleó, A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026609 · Cited by 150 · cited 1× · see citing works
“Despite the fact that tau and α-synuclein are distinct proteins that contribute to different disease-specific pathologies, multiple lines of evidence suggest that tau and α-synuclein interact, modulate the aggregation of each other and coexist in pathological inclusions in human brain [103].”
BackgroundArgyrophilic grain disease: A late‐onset dementia with distinctive features among tauopathies
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Dynamic association of tau with neuronal membranes is regulated by phosphorylation
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“, N279K, N296H, P301S, S305I mutations) [33, 34].”
Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
Forrest, S. L., Kril, J. J., Stevens, C. H., Kwok, J. B., Hallupp, M., Kim, W. S., Huang, Y. M., McGinley, C. V., Werka, H., Kiernan, M. C., et al. (2017) · Brain · doi:10.1093/brain/awx328 · Cited by 148 · see citing works
Discovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes
Ait‐Bouziad, N., Lv, G., Mahul‐Mellier, A., Xiao, S., Zorludemir, G., Eliezer, D., Walz, T., & Lashuel, H. A. (2017) · Nature Communications · doi:10.1038/s41467-017-01575-4 · Cited by 147 · see citing works
Hyperphosphorylation and Cleavage at D421 Enhance Tau Secretion
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Dysregulation of RNA Binding Protein Aggregation in Neurodegenerative Disorders
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“Furthermore, in animal models pathological tau appears to be more localized to synapses compared to non-pathological tau [63], and synaptosomes isolated from human AD brains were shown to contain more phosphorylated and aggregated tau than in healthy controls [64].”
BackgroundNeuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease
Wadhwani, A. R., Affaneh, A., Van Gulden, S., & Kessler, J. A. (2019) · Annals of Neurology · doi:10.1002/ana.25455 · Cited by 142 · see citing works
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Induction of a transmissible tau pathology by traumatic brain injury
Zanier, E. R., Bertani, I., Sammali, E., Pischiutta, F., Chiaravalloti, M. A., Vegliante, G., Masone, A., Corbelli, A., Smith, D. H., Menon, D. K., et al. (2018) · Brain · doi:10.1093/brain/awy193 · Cited by 136 · cited 3× · see citing works
“AD Alzheimer’s disease AGD Argyrophylic grain disease CBD Corticobasal degeneration CSF Cerebrospinal fluid EM Electron microscopy ER Endoplasmic reticulum FGF2 Fibroblast growth factor 2 FTD Frontotemporal dementia FTDP-17 Frontotemporal dementia with Parkinsonism in chromosome 17 GAG Glycosaminoglycan HSPG Heparin s…”
BackgroundAmyloid-β Annular Protofibrils Evade Fibrillar Fate in Alzheimer Disease Brain
Lasagna‐Reeves, C. A., Glabe, C. G., & Kayed, R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.236257 · Cited by 136 · cited 1× · see citing works
“Interestingly, other disease-associated proteins, such as α-synuclein and Aβ, also have the ability to form bacteriotoxin-like annular protofibrils and pore-like structures in membranes [183, 184], suggesting that this mechanism could play a central role in unconventional secretion of several misfolded aggregating pro…”
BackgroundPre‐synaptic C‐terminal truncated tau is released from cortical synapses in Alzheimer's disease
Sokolow, S., Henkins, K. M., Bilousova, T., Gonzalez, B., Vinters, H. V., Miller, C. A., Cornwell, L., Poon, W. W., & Gylys, K. H. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.12991 · Cited by 133 · see citing works
Kouri, N., Murray, M. E., Hassan, A., Rademakers, R., Uitti, R. J., Boeve, B. F., Graff‐Radford, N. R., Wszołek, Z. K., Litvan, I., Josephs, K. A., et al. (2011) · Brain · doi:10.1093/brain/awr234 · Cited by 133 · see citing works
Neuronal exosomes reveal Alzheimer's disease biomarkers in Down syndrome
Hamlett, E. D., Goetzl, E. J., Ledreux, A., Vasilevko, V., Boger, H. A., LaRosa, A., Clark, D., Carroll, S. L., Carmona‐Iragui, M., Fortea, J., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.08.012 · Cited by 129 · see citing works
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Expression of microtubule-associated proteins MAP2 and tau in cultured rat brain oligodendrocytes
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The Role of the Lipid Bilayer in Tau Aggregation
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Nucleation-dependent Tau Filament Formation
Congdon, E. E., Kim, S., Bonchak, J., Songrug, T., Anastasios Matzavinos, A., & Kuret, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800247200 · Cited by 126 · see citing works
Soluble Aβ Promotes Wild-Type Tau Pathology<i>In Vivo</i>
Chabrier, M. A., Blurton-Jones, M., Agazaryan, A. A., Nerhus, J. L., Martinez-Coria, H., & LaFerla, F. M. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0172-12.2012 · Cited by 123 · cited 1× · see citing works
“For example, in mouse model of AD, soluble Aβ promotes development of tau pathology [75, 76].”
Tau isoform composition influences rate and extent of filament formation
Zhong, Q., Congdon, E. E., Nagaraja, H. N., & Kuret, J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.364067 · Cited by 122 · see citing works
Neuropathology of Pick’s disease
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Extracellular Monomeric Tau Is Internalized by Astrocytes
Perea, J. R., López, E., Díez-Ballesteros, J. C., Ávila, J., Hernández, F., & Bolós, M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00442 · Cited by 114 · see citing works
DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins
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mTor mediates tau localization and secretion: implication for Alzheimer’s disease
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“Moreover, expression and activities of several enzymes participating in generation and modification of sulfated glycosaminoglycans, particularly heparan sulfate sulfotransferases, have been reported to be altered in AD brain and to affect accumulation of phosphorylated tau species [228, 229].”
BackgroundChronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice
Zhu, Y., Zhan, G., Fenik, P., Brandes, M., Bell, P., François, N., Shulman, K., & Veasey, S. C. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0275-18.2018 · Cited by 106 · see citing works
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Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112841 · Cited by 509 · see citing works
“At the protein level, K257T, G272V, P301L, V337M, and R406W mutations alter the binding properties of the microtubule, and N279K, N296H, P301S, S305I mutations at the RNA level shifts the splicing towards overproduction of 4R tau [97].”
BackgroundThe expanding amyloid family: Structure, stability, function, and pathogenesis
Sawaya, M. R., Hughes, M. P., Rodriguez, J. A., Riek, R., & Eisenberg, D. S. (2021) · Cell · doi:10.1016/j.cell.2021.08.013 · Cited by 475 · see citing works
Role of tau protein in Alzheimer’s disease: The prime pathological player
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Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons
Ruan, Z., Pathak, D., Venkatesan Kalavai, S., Yoshii-Kitahara, A., Muraoka, S., Bhatt, N., Takamatsu-Yukawa, K., Hu, J., Wang, Y., Hersh, S., et al. (2021) · Brain · doi:10.1093/brain/awaa376 · Cited by 283 · see citing works
“secreted primarily in free form, while a minor fraction of tau is found in EVs as observed in the CSF or blood of control subjects and Alzheimer’s disease patients (Arai et al., 1998; Saman et al., 2012; Zetterberg et al., 2013; Fiandaca et al., 2015; Ruan and Ikezu, 2019; Brunello et al., 2020).”
BackgroundAcetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
Caballero, B., Bourdenx, M., Luengo, E., Diaz, A., Sohn, P. D., Chen, X., Wang, C., Juste, Y. R., Wegmann, S., Patel, B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22501-9 · Cited by 223 · see citing works
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Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease
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Role of natural products for the treatment of Alzheimer’s disease
Noori, T., Dehpour, A. R., Sureda, A., Sobarzo-Sanchez, E., & Shirooie, S. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.173974 · Cited by 141 · see citing works
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“309 As TAU spreading has been shown to be mediated (among other pathways) via EVs (reviewed, e.g., in 310 ),theseinitialresultssupportourhypothesisthatratherindividual TAU isoforms mediate TAU toxicity in disease context.”
BackgroundBiomolecular condensates can both accelerate and suppress aggregation of α-synuclein
Lipiński, W. P., Visser, B. S., Robu, I., Fakhree, M. A. A., Lindhoud, S., Claessens, M. M. A. E., & Spruijt, E. (2022) · Science Advances · doi:10.1126/sciadv.abq6495 · Cited by 134 · see citing works
“This has been observed for amyloid-β(1-42) (33) and may occur also for other amyloidogenic proteins.”
Extracellular Monomeric Tau Is Internalized by Astrocytes
Perea, J. R., López, E., Díez-Ballesteros, J. C., Ávila, J., Hernández, F., & Bolós, M. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00442 · Cited by 114 · see citing works
Tilavonemab in early Alzheimer’s disease: results from a phase 2, randomized, double-blind study
Florian, H., Wang, D., Arnold, S. E., Boada, M., Guo, Q., Jin, Z., Zheng, H., Fisseha, N., Kalluri, H. V., Rendenbach‐Mueller, B., et al. (2023) · Brain · doi:10.1093/brain/awad024 · Cited by 137 · see citing works
“Further research is needed to understand the cellular mechanisms involved in the secretion and spreading of tau aggregates between cells.(7)”
BackgroundLimorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 162 · see citing works
Tau deposition patterns are associated with functional connectivity in primary tauopathies
Franzmeier, N., Brendel, M., Beyer, L., Slemann, L., Kovács, G. G., Arzberger, T., Kurz, C., Respondek, G., Ječmenica‐Lukić, M., Biel, D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28896-3 · Cited by 112 · see citing works
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
Perea, J. R., Bolós, M., & Ávila, J. (2020) · Biomolecules · doi:10.3390/biom10101439 · Cited by 127 · see citing works
“Propagation commonly involves the monomer and oligomer forms of tau, which are susceptible to aberrant folding and post-translational modifications such as truncation and phosphorylation [118].”
BackgroundTau Isoforms: Gaining Insight into MAPT Alternative Splicing
Corsi, A., Bombieri, C., Valenti, M. T., & Romanelli, M. G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315383 · Cited by 118 · see citing works
“Conversely, under pathological conditions, this mechanism contributes to the spread of altered forms of Tau across different brain areas and thus to the spatio-temporal disease progression in tauopathies [65,66].”
BackgroundThe effect of insomnia on development of Alzheimer’s disease
Sadeghmousavi, S., Eskian, M., Rahmani, F., & Rezaei, N. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01960-9 · Cited by 113 · see citing works
Role of Chemokines in the Development and Progression of Alzheimer’s Disease
Wojcieszak, J., Kuczyńska, K., & Zawilska, J. B. (2022) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02047-1 · Cited by 97 · see citing works
“Additionally, pathological tau can be secreted to extracellular space and enter surrounding neurons or glial cells further impairing axonal transport and causing neuronal synaptic loss thus contributing to progression of the disease (Brunello et al. 2019).”
BackgroundSynaptic tau: A pathological or physiological phenomenon?
Robbins, M., Clayton, E. L., & Schierle, G. S. K. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01246-y · Cited by 117 · see citing works
“It is thus interesting to note that several endocytosisrelated pathways are involved in Tau trafficking and thus may explain why Tau pathology is linked to these different pathways (for a review see [50].”
BackgroundPossible Mechanisms of Tau Spread and Toxicity in Alzheimer’s Disease
Zhang, H., Cao, Y., Ma, L., Wei, Y., & Li, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.707268 · Cited by 104 · see citing works
Tau as a Biomarker of Neurodegeneration
Holper, S., Watson, R., & Yassi, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137307 · Cited by 114 · see citing works
“Specifically, Aβmay actively drive the secretion of tau from the neuron, accounting for the pathological CSF tau concentrations seen early in AD pathogenesis, before frank neurodegeneration [95].”
BackgroundHamano, T., Enomoto, S., Shirafuji, N., Ikawa, M., Yamamura, O., Yen, S.-H. C., & Nakamoto, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147475 · Cited by 115 · see citing works
“At present, it is unclear which of the above mechanisms are involved in tau synaptic release, and whether the same mechanism is responsible for physiological tau synaptic release and pathological tau synaptic release [60].”
BackgroundShulman, M. B., Kong, J., O'Gorman, J. T., Ratti, E., Rajagovindan, R., Viollet, L., Huang, E., Sharma, S., Racine, A. M., Czerkowicz, J., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00523-w · Cited by 100 · see citing works
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“and displaying the prion-like characteristics of Tau pathology (Brunello et al., 2020).”
BackgroundKim, O. Y., & Song, J. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122356 · Cited by 96 · see citing works
Cerebrovascular disease promotes tau pathology in Alzheimer’s disease
Laing, K. K., Simoes, S., Baena-Caldas, G. P., Lao, P. J., Kothiya, M., Igwe, K. C., Chesebro, A. G., Houck, A. L., Pedraza, L., Hernandez, A. I., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa132 · Cited by 93 · see citing works
Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies
Limanaqi, F., Biagioni, F., Gambardella, S., Familiari, P., Frati, A., & Fornai, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21083028 · Cited by 93 · see citing works
“Sci. 2020, 21, 3028; doi:10.3390/ijms21083028 www.mdpi.com/journal/ijms of specific disease-associated proteins include alpha-synuclein (α-syn) in synucleinopathies such as PD and multiple system atrophy (MSA), amyloid-beta (Aβ) and tau in AD, polyglutamine-expanded huntingtin in HD, TAR-DNA-binding protein of 43 kDa…”
BackgroundInfluentialVesga-Jiménez, D. J., Martin, C., Barreto, G. E., Aristizábal-Pachón, A. F., Pinzón, A. M., & González, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052577 · Cited by 100 · see citing works
“Abnormal tangles in the brain are formed with tau protein in the hyperphosphorylated form they are unable to bind to tubulin and microtubules, disrupting the neuronal cytoskeleton, as well as reducing microtubules and neurofilaments [187,188].”
BackgroundLiu, S., Hossinger, A., Heumüller, S.-E., Hornberger, A., Buravlova, O., Konstantoulea, K., Müller, S. A., Paulsen, L., Rousseau, F., Schymkowitz, J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25855-2 · Cited by 72 · see citing works
Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies
Silva, M. C., & Haggarty, S. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238948 · Cited by 87 · see citing works
Rai, S. K., Khanna, R., Avni, A., & Mukhopadhyay, S. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2216338120 · Cited by 76 · see citing works
“The truncations of tau protein and human PrP (23-231) were created using full-length variants of the respective constructs.”
BackgroundMethodProteostasis Disturbances and Inflammation in Neurodegenerative Diseases
Sonninen, T.-M., Goldsteins, G., Laham-Karam, N., Koıstınaho, J., & Lehtonen, Š. (2020) · Cells · doi:10.3390/cells9102183 · Cited by 84 · see citing works
“Another hallmark of AD pathology, tauopathy, has been demonstrated to spread between the brain cells by direct secretion, ectosomal, and exosomal mechanisms [87].”
BackgroundThe extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Yuste‐Checa, P., Trinkaus, V. A., Riera-Tur, I., Imamoglu, R., Schaller, T., Wang, H., Dudanova, I., Hipp, M. S., Bracher, A., & Hartl, F. U. (2021) · Nature Communications · doi:10.1038/s41467-021-25060-1 · Cited by 76 · see citing works
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A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies
Imbimbo, B. P., Ippati, S., Watling, M., & Balducci, C. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12453 · Cited by 72 · see citing works
Microglia: Friend and foe in tauopathy
Odfalk, K. F., Bieniek, K. F., & Hopp, S. C. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102306 · Cited by 60 · see citing works
Kazim, S. F., Sharma, A., Saroja, S. R., Seo, J. H., Larson, C. S., Ramakrishnan, A., Wang, M., Blitzer, R. D., Shen, L., Peña, C. J., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.02.973 · Cited by 72 · see citing works
Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration
Boyarko, B., & HOOK, V. Y. H. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.702788 · Cited by 74 · see citing works
Role of the Lipid Membrane and Membrane Proteins in Tau Pathology
Bok, E., Leem, E., Lee, B.-R., Lee, J. M., Yoo, C. J., Lee, E. M., & Kim, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.653815 · Cited by 61 · see citing works
Targeting tau in Alzheimer's disease: from mechanisms to clinical therapy
Ye, J., Wan, H., Chen, S., & Liu, G. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.385847 · Cited by 69 · see citing works
“…and AD, thereby supporting a critical involvement of glial cells and neuroinflammation in tauopathies (Zhong et al., 2017; Pimenova et al., 2018; Brunello et al., 2020; Wang et al., 2020b, 2022; Griciuc and Tanzi, 2021; Haass, 2021; Jin et al., 2021; Lee et al., 2021; Wang and Ye, 2021; Zhao et…”
Neuropathological assessment of the Alzheimer spectrum
Jellinger, K. A. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02232-9 · Cited by 82 · see citing works
Li, Z., Yin, B., Zhang, S., Lan, Z., & Zhang, L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115817 · Cited by 54 · see citing works
Lim, D. W., Lee, J., Lee, C.-H., & Kim, Y. T. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011223 · Cited by 66 · see citing works
“Tau proteins contribute to maintaining the morphology of neurons, particularly by stabilizing microtubules within axons and dendrites to support cellular structures [31].”
BackgroundFranzmeier, N., Roemer, S. N., Bernhardt, A. M., Dehsarvi, A., Dewenter, A., Steward, A., Biel, D., Frontzkowski, L. K., Zhu, Z., Gnörich, J. S., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00822-3 · Cited by 68 · see citing works
“CSF p-tau increases have previously been shown to be more closely linked to PET-assessed fibrillar Aβ than to fibrillar tau pathology [58] and to reflect Aβ-associated active secretion of newly synthesized p-tau molecules, rather than passive spill out from dead neurons [43, 59].”
Franzmeier, N., Dehsarvi, A., Steward, A., Biel, D., Dewenter, A., Roemer, S. N., Wagner, F., Groß, M., Brendel, M., Moscoso, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44374-w · Cited by 61 · see citing works
Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease
Padmanabhan, P., Kneynsberg, A., & Götz, J. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00531-y · Cited by 55 · see citing works
Tau and Membranes: Interactions That Promote Folding and Condensation
Sallaberry, C. A., Voss, B. J., Majewski, J. P., Biernat, J., Mandelkow�, E., Chi, E. Y., & Zanden, C. M. V. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.725241 · Cited by 60 · see citing works
“Microtubule binding is commonly ascribed to the RD, but it should be noted that strong binding requires components of the flanking PXXP and C-terminal domains (Butner and Kirschner, 1991; Gustke et al., 1994; Preuss et al., 1997).”
BackgroundHsp40s play complementary roles in the prevention of tau amyloid formation
Irwin, R., Faust, O., Petrovic, I. M., Wolf, S. G., Hofmann, H., & Rosenzweig, R. (2021) · eLife · doi:10.7554/elife.69601 · Cited by 66 · see citing works
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Reactivated endogenous retroviruses promote protein aggregate spreading
Liu, S., Heumüller, S.-E., Hossinger, A., Müller, S. A., Buravlova, O., Lichtenthaler, S. F., Denner, P., & Vorberg, I. M. (2023) · Nature Communications · doi:10.1038/s41467-023-40632-z · Cited by 48 · see citing works
The evolving landscape of Alzheimer’s disease therapy: From Aβ to tau
Courade, J., Zetterberg, H., Höglinger, G. U., & Dewachter, I. (2025) · Cell · doi:10.1016/j.cell.2025.11.033 · Cited by 52 · see citing works
Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau
de Gérando, A. M., Welikovitch, L. A., Khasnavis, A., Commins, C., Glynn, C. A., Chun, J. E., Perbet, R., & Hyman, B. T. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02600-1 · Cited by 52 · see citing works
“Considering the several different pathways of pathological tau secretion and spreading [10] as well as the involvement of neuronal activity in tau pathology progression [12, 46, 63], the rate of progression of SARK and HMW tau could be influenced by multiple, yet unexplored, biological factors.”
BackgroundRecent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer’s Disease
Singh, R., Panghal, A., Jadhav, K., Thakur, A., Verma, R. K., Singh, C., Goyal, M., Kumar, J., & Namdeo, A. G. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04256-8 · Cited by 47 · see citing works
“These fundamental mechanisms have been used as therapeutic targets in the treatment of tau related pathologies and other neurodegenerative diseases [132, 133].”
Huang, Y., Driedonks, T. A. P., Cheng, L., Turchinovich, A., Rajapaksha, H., Arab, T., Powell, B. H., Pletniková, O., Redding‐Ochoa, J., Troncoso, J. C., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220322 · Cited by 55 · see citing works
“EVs have been widely reported to propagate misfolded tau in neurodegenerative disease [15, 44].”
BackgroundTong, B. C., Huang, S., Wu, A. J., Iyaswamy, A., Ho, O. K.-Y., Kong, A. H.-Y., Sreenivasmurthy, S. G., Zhu, Z., Su, C.-F., Liu, J., et al. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00871-6 · Cited by 49 · see citing works
“It is believed that pathological tau is liberated from cells via direct secretion of tau clusters, ectosomes, or exosomes or via junctions with adjacent cells [66].”
The pleiotropic roles of autophagy in Alzheimer’s disease: From pathophysiology to therapy
Festa, B. P., Barbosa, A. D., Rob, M., & Rubinsztein, D. C. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.07.011 · Cited by 41 · see citing works
Modulating disease-relevant tau oligomeric strains by small molecules
Cascio, F. L., García, S., Montalbano, M., Puangmalai, N., McAllen, S., Pace, A., Piccionello, A. P., & Kayed, R. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014630 · Cited by 51 · see citing works
“Therefore, more investigations are needed to better understand how tau is released in the extracellular space to be then internalized into neighboring or anatomically connected cells and sequentially template for further aggregation within those cells (74, 75).”
BackgroundDas, R., Balmik, A., & Chinnathambi, S. (2020) · ASN Neuro · doi:10.1177/1759091420981204 · Cited by 41 · see citing works
“The Tau NFTs containing neurons flag phosphatidylserine on its surface and activates the signaling cascade for apoptosis (Brunello et al., 2020).”
BackgroundTau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis
Agnello, L., Colletti, T., Sasso, B. L., Vidali, M., Spataro, R., Gambino, C. M., Giglio, R. V., Piccoli, T., Bivona, G., Bella, V. L., et al. (2021) · European Journal of Neurology · doi:10.1111/ene.14789 · Cited by 42 · see citing works
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Marx, G. A., Koenigsberg, D., McKenzie, A. T., Kauffman, J., Hanson, R. W., Whitney, K. R., Signaevsky, M., Prastawa, M. W., Iida, M. A., White, C. L., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01457-x · Cited by 43 · see citing works
“This approach to measuring disease burden has the theoretical potential to capture mechanisms of p-tau spread through a given region, which is currently under investigation by several other groups [47–54].”
BackgroundXiao, D., Li, J., Ren, Z., Dai, M., Jiang, Y., Qiu, T., Zhang, H., Chen, Y., Zhang, Y., Zhang, Y., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14158 · Cited by 36 · see citing works
“57 Such detrimental effects could be amplified by the inefficient glymphatic waste clearance, 58 Some limitations should be mentioned for this study.”
BackgroundUnconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes
Meldolesi, J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.877344 · Cited by 43 · see citing works
Metabolomics in degenerative brain diseases
Escobar, M. Q., Pontes, J. G. D. M., & Tasić, L. (2021) · Brain Research · doi:10.1016/j.brainres.2021.147704 · Cited by 40 · see citing works
The chaperone Clusterin in neurodegeneration−friend or foe?
Yuste‐Checa, P., Bracher, A., & Hartl, F. U. (2022) · BioEssays · doi:10.1002/bies.202100287 · Cited by 36 · see citing works
“reach the extracellular environment via release from dying cells or upon active secretion by neurons, which may occur through a transsynaptic mechanism[8] or in a manner facilitated by chaperones, such as the HSP40 protein DnaJC5.”
BackgroundMelatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders
Loh, D., & Reiter, R. J. (2021) · Antioxidants · doi:10.3390/antiox10091483 · Cited by 43 · see citing works
Tau internalization: A complex step in tau propagation
Zhao, J., Wu, H., & Tang, X. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101272 · Cited by 46 · see citing works
Advanced nano delivery system for stem cell therapy for Alzheimer's disease
Pan, Y., Li, L., Cao, N., Liao, J., Chen, H., & Zhang, M. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122852 · Cited by 32 · see citing works
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Brain Fog: a Narrative Review of the Most Common Mysterious Cognitive Disorder in COVID-19
Mir, M. A. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03715-y · Cited by 37 · see citing works
“Tau aggregates have the ability to spread from cell to cell, causing targeted misfolding and aggregation of healthy tau molecules in previously healthy cells, causing this in a manner similar to prion infection aims to spread tau pathology in different regions of the brain [109, 110].”
Astrocytes in depression and Alzheimer’s disease
Liao, Y., Xing, Q., Li, Q., Zhang, J., Pan, R., & Yuan, Z. (2021) · Frontiers of Medicine · doi:10.1007/s11684-021-0875-0 · Cited by 44 · see citing works
The propagation mechanisms of extracellular tau in Alzheimer’s disease
Wei, Y., Liu, M., & Wang, D. (2021) · Journal of Neurology · doi:10.1007/s00415-021-10573-y · Cited by 39 · see citing works
“Extracellular tau may mediate tau spreading and serve as a biomarker for AD [2].”
BackgroundA dynamical systems approach for multiscale synthesis of Alzheimer’s pathogenesis
Rollo, J. L., Crawford, J. W., & Hardy, J. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.018 · Cited by 30 · see citing works
Dysfunctional microglia and tau pathology in Alzheimer’s disease
Ayyubova, G. (2022) · Reviews in the Neurosciences · doi:10.1515/revneuro-2022-0087 · Cited by 35 · see citing works
Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration
Li, W., & Li, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00407-y · Cited by 35 · see citing works
“Tau has physiological functions of stabilizing microtubules and maintaining axonal transport in highly polarized neurons [73].”
BackgroundRoles of the cytoskeleton in human diseases
Li, M., Peng, L., Wang, Z.-M., Liu, L.-J., Cao, M., Cui, J., Wu, F.-Z., & Yang, J. (2023) · Molecular Biology Reports · doi:10.1007/s11033-022-08025-5 · Cited by 31
Single-cell spatial proteomic imaging for human neuropathology
Vijayaragavan, K., Cannon, B. J., Tebaykin, D., Bosse, M. M., Baranski, A., Oliveria, J. P., Bukhari, S. A., Mrdjen, D., Corces, M. R., McCaffrey, E., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01465-x · Cited by 37 · see citing works
“For instance, immunogenicity towards Aβ or Tau oligomers in CN and CIND could vary from ADD samples [52, 58, 59], or ADD may have a more reactive microglial-dependent immune response relative to those present in the CN and CIND hippocampus [60].”
Vieweg, S., Mahul-Mellier, A.-L., Ruggeri, F., Riguet, N., Deguire, S. M., Chiki, A., Cendrowska, U., Dietler, G., & Lashuel, H. (2021) · bioRxiv · doi:10.1101/2021.02.15.431207 · Cited by 31 · see citing works
“Several studies have shown that the secretion and cell-to-cell propagation of protein aggregates is mediated by their interactions with cell membranes and other membranous structures [116, 117].”
BackgroundTau in Alzheimer’s Disease: Pathological Alterations and an Attractive Therapeutic Target
Gu, J., & Liu, F. (2020) · Current Medical Science · doi:10.1007/s11596-020-2282-1 · Cited by 38 · see citing works
Altered amyloid-β and tau proteins in neural-derived plasma exosomes in obstructive sleep apnea
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Sastre, A. A., Montoro, M. L., Lacerda, H. M., Llavero, F., & Zugaza, J. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094425 · Cited by 36 · see citing works
Amro, Z., Yool, A. J., & Collins‐Praino, L. E. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100242 · Cited by 37 · see citing works
Atabi, F., Moassesfar, M., Nakhaie, T., Bagherian, M., Hosseinpour, N., & Hashemi, M. (2025) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-025-01930-2 · Cited by 24 · see citing works
“These aggregates disrupt neuronal function by sequestering normal tau and other microtubule-associated proteins [65] (Fig.”
Galpern, W. R., Triana‐Baltzer, G., Li, L., Kolen, K. V., Timmers, M., Haeverans, K., Janssens, L., Kolb, H. C., Nandy, P., Aida, K., et al. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.163 · Cited by 38 · see citing works
“However, the mechanism of tau spread is not known; it is possible that alternative mechanisms such as tunneling nanotubes or exosomes may be relevant (12), in which case tau seeds would evade the ISF where the antibody is presumed to act.”
An Overview of Astrocyte Responses in Genetically Induced Alzheimer’s Disease Mouse Models
Spanos, F., & Liddelow, S. A. (2020) · Cells · doi:10.3390/cells9112415 · Cited by 31 · see citing works
Congdon, E. E., Jiang, Y., & Sigurdsson, E. M. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.12.002 · Cited by 37 · see citing works
Role of the endolysosomal pathway and exosome release in tau propagation
Yan, M., & Zheng, T. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104988 · Cited by 34 · see citing works
Carbamate as a potential anti‐Alzheimer's pharmacophore: A review
Singh, Y. P., Kumar, N., Chauhan, B. S., & Garg, P. (2023) · Drug Development Research · doi:10.1002/ddr.22113 · Cited by 36 · see citing works
“But, under extreme conditions, hyperphosphorylated tau loses its microtubule ‐ stabilizing and axonal transport purpose (Brunello et al., 2020).”
BackgroundCerebrospinal fluid: A specific biofluid for the biosensing of Alzheimer's diseases biomarkers
Mirzaie, A., Nasrollahpour, H., Khalilzadeh, B., Jamali, A., Spiteri, R., Yousefi, H., Isildak, I., & Rahbarghazi, R. (2023) · Trends in Analytical Chemistry (TrAC) · doi:10.1016/j.trac.2023.117174 · Cited by 26 · see citing works
α– Linolenic acid modulates phagocytosis and endosomal pathways of extracellular Tau in microglia
Desale, S. E., & Chinnathambi, S. (2021) · Cell Adhesion & Migration · doi:10.1080/19336918.2021.1898727 · Cited by 63 · see citing works
“mechanisms have the tendency to propagate the disease [27,58,59].”
BackgroundEimer, W. A., Rodriguez, A. S., DeFao, M. T., Ehricke, S., Park, J., Kumar, D. K. V., Shanmugam, N. K. N., Singh, S., Sawhney, T., Moir, R. D., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02157-0 · Cited by 29 · see citing works
Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses
Kadamangudi, S., Marcatti, M., Zhang, W.-R., Fracassi, A., Kayed, R., Limon, A., & Taglialatela, G. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02839-2 · Cited by 25 · see citing works
Oatman, S. R., Reddy, J. S., Quicksall, Z., Carrasquillo, M. M., Wang, X., Liu, C., Yamazaki, Y., Nguyen, T., Malphrus, K. G., Heckman, M. G., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00592-2 · Cited by 25 · see citing works
Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology
Han, F., Lee, J., Chen, X., Ziontz, J., Ward, T. J., Landau, S. M., Baker, S. L., Harrison, T. M., Jagust, W. J., & Initiative, A. D. N. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14296 · Cited by 42 · see citing works
“67 In short, global brain activity and specific neural and physiological factors play a critical role insupportingCSFflowandthuscouldaffectADprogressionbymoder-ating the “accumulation-removal balance” of toxic proteins, such as A β and tau.”
Moreira, L., Costa, C., Pires, J., Teixeira, J. P., & Fraga, S. (2021) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2021.108385 · Cited by 34 · see citing works
Cathepsin D: A Candidate Link between Amyloid ?-protein and Tauopathy in Alzheimer Disease
Suire, C. N., & Leissring, M. A. (2021) · Journal of Experimental Neurology · doi:10.33696/neurol.2.029 · Cited by 14 · see citing works
“Among several identified trafficking mechanisms, endogenous tau has been shown to be secreted via unconventional protein secretion pathways from primary neurons [26-31].”
BackgroundKrawczuk, D., Kulczyńska‐Przybik, A., & Mroczko, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158132 · Cited by 26 · see citing works
“Tau is a soluble protein that occurs in six main isoforms in the human central nervous system (CNS) [48].”
BackgroundAutophagy-Related Pathways in Vesicular Unconventional Protein Secretion
Noh, S. H., Kim, Y. J., & Lee, M. G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.892450 · Cited by 29 · see citing works
“The tau secretion through the UPS pathway involves both non-vesicular and vesicular mechanisms (Brunello et al., 2020); and several recent studies suggest that autophagy machinery participates in the vesicular routemediated tau secretion (Mohamed et al., 2014; Kang et al., 2019; Chen et al., 2020).”
BackgroundTashima, T. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14020411 · Cited by 26 · see citing works
“In fact: (i) some tau proteins are present in exosomes secreted from cells (Figure 7) [18].”
BackgroundInfluentialFonseca, C., Ettcheto, M., Bicker, J., Fernandes, M. J., Falcão, A. C., Camins, A., & Fortuna, A. C. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101998 · Cited by 26 · see citing works
- Authors
- Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Huttunen, Henri J.
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2019-10-30
- Volume
- 77
- Issue
- 9
- Pages
- 1721-1744
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- PMC
- PMC7190606
- OpenAlex
- W2982627322
- Cited by
- 304
- References
- 267
- Citations by year
- 2026: 36 · 2025: 45 · 2024: 56 · 2023: 38 · 2022: 46 · 2021: 57 · 2020: 25 · 2019: 1
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cellular and Molecular Life Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, cc-by)
- Funders
- Academy of Finland (296409)
- Alfred Kordelinin Säätiö
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tauopathy, tau secretion, cell-to-cell transmission, prion-like propagation, tau aggregation, exosomes, ectosome, vesicular secretion, extracellular tau, endocytosis, phagocytosis, pinocytosis, Alzheimer's disease, frontotemporal lobar degeneration, neurodegeneration
- MeSH terms
- Animals, Humans, tau Proteins, Disease Progression, Tauopathies, Protein Aggregation, Pathological
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