pubmed.ncbi.nlm.nih.gov

Mechanisms of secretion and spreading of pathological tau protein - PubMed

Review

Mechanisms of secretion and spreading of pathological tau protein

Cecilia A Brunello et al. Cell Mol Life Sci. 2020 May.

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.

Keywords: Aggregation; Amyloid; Extracellular vesicles; Prion; Propagation; Tau; Unconventional protein secretion.

PubMed Disclaimer

Conflict of interest statement

HJH is an employee and a shareholder of Herantis Pharma Plc, which is not related to the contents of this review.

Figures

Fig. 1
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. 2
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)

Similar articles

Cited by

References

    1. Aamodt EJ, Williams RC., Jr Microtubule-associated proteins connect microtubules and neurofilaments in vitro. Biochemistry. 1984;23(25):6023–6031. doi: 10.1021/bi00320a019. - DOI - PubMed
    1. Bertrand A, et al. Non-invasive, in vivo monitoring of neuronal transport impairment in a mouse model of tauopathy using MEMRI. Neuroimage. 2013;64:693–702. doi: 10.1016/j.neuroimage.2012.08.065. - DOI - PMC - PubMed
    1. Seitz A, Kojima H, Oiwa K, Mandelkow EM, Song YH, Mandelkow E. Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J. 2002;21(18):4896–4905. doi: 10.1093/emboj/cdf503. - DOI - PMC - PubMed
    1. Zhang B, et al. Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy. J Neurosci. 2004;24(19):4657–4667. doi: 10.1523/JNEUROSCI.0797-04.2004. - DOI - PMC - PubMed
    1. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J Cell Biol. 1998;143(3):777–794. doi: 10.1083/jcb.143.3.777. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources