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Int. J. Mol. Sci. 2018, 19(3), 663;

Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles

Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA
Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 21 January 2018 / Revised: 10 February 2018 / Accepted: 20 February 2018 / Published: 27 February 2018
(This article belongs to the Special Issue Tau Function and Dysfunctional Tauopathies)
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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. View Full-Text
Keywords: Alzheimer’s disease; biomarkers; cerebrospinal fluid; exosomes; iPSCs; neuron; plasma Alzheimer’s disease; biomarkers; cerebrospinal fluid; exosomes; iPSCs; neuron; plasma

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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. Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int. J. Mol. Sci. 2018, 19, 663.

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