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Mechanisms of secretion and spreading of pathological tau protein. | LitMetric

Mechanisms of secretion and spreading of pathological tau protein.

Cell Mol Life Sci

Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland.

Published: May 2020

AI Article Synopsis

  • Misfolded tau protein accumulates in the brain and is a key feature of tauopathies like Alzheimer’s disease, where it propagates from cell to cell in a prion-like manner, causing further misfolding in healthy tau molecules.* -
  • The transfer of tau aggregates involves complex and not fully understood mechanisms, which can include both vesicular and non-vesicular pathways, allowing tau to be secreted in various forms, including free proteins and vesicles.* -
  • As extracellular tau can be taken up by nearby neurons and glial cells, this suggests a broader mechanism for disease progression in tauopathies and other neurodegenerative diseases.*

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190606PMC
http://dx.doi.org/10.1007/s00018-019-03349-1DOI Listing

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