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Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles.
Int J Mol Sci. 2018 Feb 27; 19(3)IJ

Abstract

Progressive cerebral accumulation of tau aggregates is a defining feature of Alzheimer's disease (AD). A popular theory that seeks to explain the apparent spread of neurofibrillary tangle pathology proposes that aggregated tau is passed from neuron to neuron. Such a templated seeding process requires that the transferred tau contains the microtubule binding repeat domains that are necessary for aggregation. While it is not clear how a protein such as tau can move from cell to cell, previous reports have suggested that this may involve extracellular vesicles (EVs). Thus, measurement of tau in EVs may both provide insights on the molecular pathology of AD and facilitate biomarker development. Here, we report the use of sensitive immunoassays specific for full-length (FL) tau and mid-region tau, which we applied to analyze EVs from human induced pluripotent stem cell (iPSC)-derived neuron (iN) conditioned media, cerebrospinal fluid (CSF), and plasma. In each case, most tau was free-floating with a small component inside EVs. The majority of free-floating tau detected by the mid-region assay was not detected by our FL assays, indicating that most free-floating tau is truncated. Inside EVs, the mid-region assay also detected more tau than the FL assay, but the ratio of FL-positive to mid-region-positive tau was higher inside exosomes than in free solution. These studies demonstrate the presence of minute amounts of free-floating and exosome-contained FL tau in human biofluids. Given the potential for FL tau to aggregate, we conclude that further investigation of these pools of extracellular tau and how they change during disease is merited.

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Authors+Show Affiliations

Guix FX
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. trescomacatorze@gmail.com.
Corbett GT
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. gtcorbett@bwh.harvard.edu.
Cha DJ
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. dcha1@bwh.harvard.edu.
Mustapic M
Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA. maja.mustapic@nih.gov.
Liu W
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. wliu@bwh.harvard.edu.
Mengel D
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. dmengel@partners.org.
Chen Z
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. zhicheng.chen@gmail.com.
Aikawa E
Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. eaikawa@bwh.harvard.edu.
Young-Pearse T
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Kapogiannis D
Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA. kapogiannisd@mail.nih.gov.
Selkoe DJ
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. dselkoe@bwh.harvard.edu.
Walsh DM
Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. dwalsh3@bwh.harvard.edu.

MeSH

AgedAged, 80 and overAllelesAlzheimer DiseaseApolipoproteins EBiomarkersBrainCase-Control StudiesCell DifferentiationCognitive DysfunctionExosomesExtracellular VesiclesFemaleHumansInduced Pluripotent Stem CellsMaleNeuronsProtein AggregatesProtein Aggregation, Pathologicaltau Proteins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29495441

Citation

Guix, Francesc X., et al. "Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles." International Journal of Molecular Sciences, vol. 19, no. 3, 2018.
Guix FX, Corbett GT, Cha DJ, et al. Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int J Mol Sci. 2018;19(3).
Guix, F. X., Corbett, G. T., Cha, D. J., Mustapic, M., Liu, W., Mengel, D., Chen, Z., Aikawa, E., Young-Pearse, T., Kapogiannis, D., Selkoe, D. J., & Walsh, D. M. (2018). Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. International Journal of Molecular Sciences, 19(3). https://doi.org/10.3390/ijms19030663
Guix FX, et al. Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int J Mol Sci. 2018 Feb 27;19(3) PubMed PMID: 29495441.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. AU - Guix,Francesc X, AU - Corbett,Grant T, AU - Cha,Diana J, AU - Mustapic,Maja, AU - Liu,Wen, AU - Mengel,David, AU - Chen,Zhicheng, AU - Aikawa,Elena, AU - Young-Pearse,Tracy, AU - Kapogiannis,Dimitrios, AU - Selkoe,Dennis J, AU - Walsh,Dominic M, Y1 - 2018/02/27/ PY - 2018/01/21/received PY - 2018/02/10/revised PY - 2018/02/20/accepted PY - 2018/3/3/entrez PY - 2018/3/3/pubmed PY - 2018/8/28/medline KW - Alzheimer’s disease KW - biomarkers KW - cerebrospinal fluid KW - exosomes KW - iPSCs KW - neuron KW - plasma JF - International journal of molecular sciences JO - Int J Mol Sci VL - 19 IS - 3 N2 - Progressive cerebral accumulation of tau aggregates is a defining feature of Alzheimer's disease (AD). A popular theory that seeks to explain the apparent spread of neurofibrillary tangle pathology proposes that aggregated tau is passed from neuron to neuron. Such a templated seeding process requires that the transferred tau contains the microtubule binding repeat domains that are necessary for aggregation. While it is not clear how a protein such as tau can move from cell to cell, previous reports have suggested that this may involve extracellular vesicles (EVs). Thus, measurement of tau in EVs may both provide insights on the molecular pathology of AD and facilitate biomarker development. Here, we report the use of sensitive immunoassays specific for full-length (FL) tau and mid-region tau, which we applied to analyze EVs from human induced pluripotent stem cell (iPSC)-derived neuron (iN) conditioned media, cerebrospinal fluid (CSF), and plasma. In each case, most tau was free-floating with a small component inside EVs. The majority of free-floating tau detected by the mid-region assay was not detected by our FL assays, indicating that most free-floating tau is truncated. Inside EVs, the mid-region assay also detected more tau than the FL assay, but the ratio of FL-positive to mid-region-positive tau was higher inside exosomes than in free solution. These studies demonstrate the presence of minute amounts of free-floating and exosome-contained FL tau in human biofluids. Given the potential for FL tau to aggregate, we conclude that further investigation of these pools of extracellular tau and how they change during disease is merited. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/29495441/Detection_of_Aggregation_Competent_Tau_in_Neuron_Derived_Extracellular_Vesicles_ DB - PRIME DP - Unbound Medicine ER -