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dc.contributor.authorCox, Kristine  Concept link
dc.contributor.authorCombs, Benjamin  Concept link
dc.contributor.authorAbdelmesih, Brenda  Concept link
dc.contributor.authorMorfini, Gerardo A.  Concept link
dc.contributor.authorBrady, Scott T.  Concept link
dc.contributor.authorKanaan, Nicholas M.  Concept link
dc.date.accessioned2016-11-30T18:46:25Z
dc.date.available2016-11-30T18:46:25Z
dc.date.issued2016-07-29
dc.identifier.citationNeurobiology of Aging 47 (2016): 113–126en_US
dc.identifier.urihttps://hdl.handle.net/1912/8556
dc.description© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Neurobiology of Aging 47 (2016): 113–126, doi:10.1016/j.neurobiolaging.2016.07.015.en_US
dc.description.abstractMisfolded tau proteins are characteristic of tauopathies, but the isoform composition of tau inclusions varies by tauopathy. Using aggregates of the longest tau isoform (containing 4 microtubule-binding repeats and 4-repeat tau), we recently described a direct mechanism of toxicity that involves exposure of the N-terminal phosphatase-activating domain (PAD) in tau, which triggers a signaling pathway that disrupts axonal transport. However, the impact of aggregation on PAD exposure for other tau isoforms was unexplored. Here, results from immunochemical assays indicate that aggregation-induced increases in PAD exposure and oligomerization are common features among all tau isoforms. The extent of PAD exposure and oligomerization was larger for tau aggregates composed of 4-repeat isoforms compared with those made of 3-repeat isoforms. Most important, aggregates of all isoforms exhibited enough PAD exposure to significantly impair axonal transport in the squid axoplasm. We also show that PAD exposure and oligomerization represent common pathological characteristics in multiple tauopathies. Collectively, these results suggest a mechanism of toxicity common to each tau isoform that likely contributes to degeneration in different tauopathies.en_US
dc.description.sponsorshipThis work was supported by NIH grants R01 AG044372 (Nicholas M. Kanaan), R01 NS082730 (Nicholas M. Kanaan and Scott T. Brady), BrightFocus Foundation (A2013364S, Nicholas M. Kanaan), the Jean P. Schultz Biomedical Research Endowment (Nicholas M. Kanaan), the Secchia Family Foundation (Nicholas M. Kanaan) and NS066942A (Gerardo Morfini).en_US
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.relation.urihttps://doi.org/10.1016/j.neurobiolaging.2016.07.015
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectTauopathyen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectOligomeren_US
dc.subjectAxonen_US
dc.subjectAggregationen_US
dc.subjectMicrotubule-associated proteinen_US
dc.subjectPathological conformationsen_US
dc.titleAnalysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibitionen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.neurobiolaging.2016.07.015


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Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International