Propagation of Tau Misfolding from the Outside to the Inside of a Cell*

By Bess Frost, R. Jacks, M. Diamond. Journal of Biological Chemistry, 2009

1,174 citations recorded by the source corpus.

Tauopathies are neurodegenerative diseases characterized by aggregation of the microtubule-associated protein Tau in neurons and glia. Although Tau is normally considered an intracellular protein, Tau aggregates are observed in the extracellular space, and Tau peptide is readily detected in the cerebrospinal fluid of patients. Tau aggregation occurs in many diseases, including Alzheimer disease and frontotemporal dementia. Tau pathology begins in discrete, disease-specific regions but eventually involves much larger areas of the brain. It is unknown how this propagation of Tau misfolding occurs. We hypothesize that extracellular Tau aggregates can transmit a misfolded state from the outside to the inside of a cell, similar to prions. Here we show that extracellular Tau aggregates, but not monomer, are taken up by cultured cells. Internalized Tau aggregates displace tubulin, co-localize with dextran, a marker of fluid-phase endocytosis, and induce fibrillization of intracellular full-length Tau. These intracellular fibrils are competent to seed fibril formation of recombinant Tau monomer in vitro. Finally, we observed that newly aggregated intracellular Tau transfers between co-cultured cells. Our data indicate that Tau aggregates can propagate a fibrillar, misfolded state from the outside to the inside of a cell. This may have important implications for understanding how protein misfolding spreads through the brains of tauopathy patients, and it is potentially relevant to myriad neurodegenerative diseases associated with protein misfolding.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/0a4694f61cb27457534006cd9f7b4e2653bcd218

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Citations in the corpus

α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. (2011, positive): “Thus, hyperphosphorylated Tau inclusions might spread via cell-to-cell transfer and trigger nucleation/aggregation in Alzheimer disease and other tauopathies (16).”
Proteopathic tau seeding predicts tauopathy in vivo (2014, background): “Several reports have implicated prion-like seeding as a key mechanism for driving tauopathy disease progression (8, 9, 18, 34, 35).”
Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer’s-like Tauopathy (2013, background): “Previous in vitro studies established that synthetic tau pffs are capable of templating the conversion of soluble tau into fibrillar aggregates in cultured cells (Frost et al., 2009; Guo and Lee, 2011; Kfoury et al., 2012).”
Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis (2016, methodology): “In summary, main preprocessing steps included: (1) motion correction, (2) perfusion-weighted images (PWI) computation, (3) intensity scaling, (4) cerebral blood flow (CBF) images calculation, (5) spatial normalization to MNI space using the registration parameters obtained for the structural T1 imag”
Brain-Gut-Microbiota Axis in Alzheimer’s Disease (2019, background): “misfolding, aggregation and transfer to other co-cultured cells were observed in vitro.(72) In addition to extracellular Aβ deposition, the protein accumulates inside neurons.”
Prion-like transmission of protein aggregates in neurodegenerative diseases (2010, result): “By contrast, another series of experiments examined the ability of aggregated tau to enter cells in cultur”
Primary age-related tauopathy (PART): a common pathology associated with human aging (2014, background): “synaptically [34, 35, 38, 46, 47, 57, 91], it is notable that PART-type pathology generally does not progress to the isocortical Braak stages (i.”
Biochemistry and cell biology of tau protein in neurofibrillary degeneration. (2012, background): “One hypothesis is that affected neurons release pathological Tau, which is taken up by neighboring cells and thus spreads the pathology in a prion-like fashion (Clavaguera et al. 2009; Frost et al. 2009).”
Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies (2016, background): “The most recent data obtained indicate that tau pathology indeed may be induced and propagated after the injection of tau oligomers or aggregates in either wild-type or mutated MAPT transgenic mice [164], and that tau aggregates can be transferred from cell to cell in vitro [164,165] and in vivo [16”