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Cited by 304Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingNeuroinflammation and Neurodegeneration Mechanisms

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Mechanisms of secretion and spreading of pathological tau protein

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Brunello, Cecilia A., Merezhko, Maria, Uronen, Riikka-Liisa, Huttunen, Henri J.·2020·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-019-03349-1PMC PMC7190606
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Abstract

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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Figures

Fig. 1 The structural basis of tau function and aggregation. a The domain structure of human tau protein. Location of the projection domain, proline-rich domain, MTBDs, and the parts of tau protein encoded by the alternatively spliced exons 2, 3 and 10 are shown on top of the longest tau isoform (2N4R, 441 aa). Below the location of key phosphorylated residues, the two hexapeptides, the two cysteines and examples of FTLD-associated mutations in the MTBDs are shown. b Microtubules (blue and green) are formed by the assembly of α- and β-tubulin dimers into protofilaments that associate laterally into hollow tubes. Tau (red) binds to the surface of microtubules interacting with α- and β-tubulin via the MTBDs. The image was prepared based on a cryo-EM structure of microtubule-associated synthetic tau (PDB: 6CVN). c Structure of a paired helical filament (PHF) fragment isolated from AD brain. The filaments are formed of anti-parallel β-sheets, with the protofilament core formed by the four MTBDs of tau. The location of the tau hexapeptide sequence is indicated. Image was prepared based on a cryo-EM structure (PDB: 5O3L)
Fig. 1 The structural basis of tau function and aggregation. a The domain structure of human tau protein. Location of the projection domain, proline-rich domain, MTBDs, and the parts of tau protein encoded by the alternatively spliced exons 2, 3 and 10 are shown on top of the longest tau isoform (2N4R, 441 aa). Below the location of key phosphorylated residues, the two hexapeptides, the two cysteines and examples of FTLD-associated mutations in the MTBDs are shown. b Microtubules (blue and green) are formed by the assembly of α- and β-tubulin dimers into protofilaments that associate laterally into hollow tubes. Tau (red) binds to the surface of microtubules interacting with α- and β-tubulin via the MTBDs. The image was prepared based on a cryo-EM structure of microtubule-associated synthetic tau (PDB: 6CVN). c Structure of a paired helical filament (PHF) fragment isolated from AD brain. The filaments are formed of anti-parallel β-sheets, with the protofilament core formed by the four MTBDs of tau. The location of the tau hexapeptide sequence is indicated. Image was prepared based on a cryo-EM structure (PDB: 5O3L)CC BY · PubMed Central
Fig. 2 Mechanisms of cell-to-cell transfer of pathological tau protein. Pathological tau conformers can be transferred between cells by multiple non-exclusive mechanisms. (1) Tau secretion directly through the PM involves clustering of tau at the PM, interaction with specific lipids in cholesterol/sphingomyelin/PI(4,5)P2-rich membrane microdomains, penetration through the PM and release from the PM facilitated by cell surface HSPGs. This unconventional tau secretion mechanism resembles the secretion of FGF2 (UPS I-like). (2) Tau is secreted in ectosomes shed from the PM. Ectosomes are larger than exosomes and also differ in their molecular composition. After their release from cells, both ectosomes and exosomes function similarly and can be fused to or endocytosed by target cells. (3) Secretion of tau in exosomes and via organelle hitchhiking. Tau can be packed in exosomes by inward budding of late endosome membrane leading to formation of intraluminal vesicles in multivesicular bodies (MVB) that can be secreted by fusion of MVB membrane with the PM. Other organelle hitch-hiking (UPS III-like) pathways possibly involved in secretion of tau and other misfolded cytosolic proteins include secretory endo-lysosomes, related to the autophagy-lysosomal pathway. The MAPS pathway promotes secretion of cytosolic misfolded proteins by chaperone-mediated capture of misfolded cytosolic proteins to the ER, followed by secretion via fusion of endo-lysosomal vesicles with the PM releasing vesicle-free tau in the extracellular space. (4) Cell-to-cell transfer of tau seeds via tunneling nanotubes that directly connect the cytosols of two neighboring cell. Regardless of the secretion pathway, tau aggregates eventually reach the cytosol of the recipient cells, allowing templated seeding of healthy tau molecules into misfolded pathological conformations. The recipient cells can then propagate the pathology further to other previously unaffected cells. It is currently unclear which ones of the above mechanisms are involved in synaptic release of tau, and whether the synaptic release of physiological and pathological forms of tau are mediated by the same mechanism(s)
Fig. 2 Mechanisms of cell-to-cell transfer of pathological tau protein. Pathological tau conformers can be transferred between cells by multiple non-exclusive mechanisms. (1) Tau secretion directly through the PM involves clustering of tau at the PM, interaction with specific lipids in cholesterol/sphingomyelin/PI(4,5)P2-rich membrane microdomains, penetration through the PM and release from the PM facilitated by cell surface HSPGs. This unconventional tau secretion mechanism resembles the secretion of FGF2 (UPS I-like). (2) Tau is secreted in ectosomes shed from the PM. Ectosomes are larger than exosomes and also differ in their molecular composition. After their release from cells, both ectosomes and exosomes function similarly and can be fused to or endocytosed by target cells. (3) Secretion of tau in exosomes and via organelle hitchhiking. Tau can be packed in exosomes by inward budding of late endosome membrane leading to formation of intraluminal vesicles in multivesicular bodies (MVB) that can be secreted by fusion of MVB membrane with the PM. Other organelle hitch-hiking (UPS III-like) pathways possibly involved in secretion of tau and other misfolded cytosolic proteins include secretory endo-lysosomes, related to the autophagy-lysosomal pathway. The MAPS pathway promotes secretion of cytosolic misfolded proteins by chaperone-mediated capture of misfolded cytosolic proteins to the ER, followed by secretion via fusion of endo-lysosomal vesicles with the PM releasing vesicle-free tau in the extracellular space. (4) Cell-to-cell transfer of tau seeds via tunneling nanotubes that directly connect the cytosols of two neighboring cell. Regardless of the secretion pathway, tau aggregates eventually reach the cytosol of the recipient cells, allowing templated seeding of healthy tau molecules into misfolded pathological conformations. The recipient cells can then propagate the pathology further to other previously unaffected cells. It is currently unclear which ones of the above mechanisms are involved in synaptic release of tau, and whether the synaptic release of physiological and pathological forms of tau are mediated by the same mechanism(s)CC BY · PubMed Central

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Citations

Cites

Research works printed but not linked: 3

  1. Liu F, Gong CX (2008) Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 3:8 · DOI · Paper page
  2. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83(13):4913–4917 · DOI · Paper page
  3. Yamada K et al (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med 211(3):387–393 · DOI

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Metadata

Authors
Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J.
Affiliations
University of Helsinki (FI)
Corresponding author
Huttunen, Henri J.
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2019-10-30
Volume
77
Issue
9
Pages
1721-1744
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-019-03349-1
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
Licence
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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