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DC Field | Value | Language |
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dc.contributor.author | STANCU, Ilie Cosmin | - |
dc.contributor.author | Vasconcelos, Bruno | - |
dc.contributor.author | Ris, Laurence | - |
dc.contributor.author | Wang, Peng | - |
dc.contributor.author | Villers, Agnès | - |
dc.contributor.author | PEERAER, Eve | - |
dc.contributor.author | Buist, Arjan | - |
dc.contributor.author | TERWEL, Dick | - |
dc.contributor.author | Baatsen, Peter | - |
dc.contributor.author | Oyelami, Tutu | - |
dc.contributor.author | Pierrot, Nathalie | - |
dc.contributor.author | Casteels, Cindy | - |
dc.contributor.author | Bormans, Guy | - |
dc.contributor.author | Kienlen-Campard, Pascal | - |
dc.contributor.author | Octave, Jean-Nöel | - |
dc.contributor.author | Moechars, Diederik | - |
dc.contributor.author | DEWACHTER, Ilse | - |
dc.date.accessioned | 2020-01-17T09:04:21Z | - |
dc.date.available | 2020-01-17T09:04:21Z | - |
dc.date.issued | 2015 | - |
dc.date.submitted | 2020-01-09T11:28:33Z | - |
dc.identifier.citation | ACTA NEUROPATHOLOGICA, 129 (6) , p. 875 -894 | - |
dc.identifier.uri | http://hdl.handle.net/1942/30336 | - |
dc.description.abstract | Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABA(A)R-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic preformed Tau fibrils in cultured primary neurons. Electrophysiological analysis in organotypic hippocampal slices of Tau transgenic mice demonstrated impaired synaptic transmission and impaired long-term potentiation following Tau-seed induced Tau-aggregation. Intracerebral injection of Tau-seeds in TauP301S mice, caused prion-like spreading of Tau-pathology through functionally connected neuroanatomical pathways. Electrophysiological analysis revealed impaired synaptic plasticity in hippocampal CA1 region 6 months after Tau-seeding in entorhinal cortex (EC). Furthermore, templated Tau aggregation impaired cognitive function, measured in the object recognition test 6 months post-seeding. In contrast, Tau-seeding in basal ganglia and subsequent spreading through functionally connected neuronal networks involved in motor control, resulted in motoric deficits reflected in clasping and impaired inverted grid hanging, not significantly affected following Tau-seeding in EC. Immunostaining, biochemical and electron microscopic analysis in the different models suggested early pathological forms of Tau, including Tau-oligomers, rather than fully mature neurofibrillary tangles (NFTs) as culprits of neuronal dysfunction. We here demonstrate for the first time using in vitro, ex vivo and in vivo models, that prion-like spreading of Tau-misfolding by Tau seeds, along unique neuronal connections, causes neuronal network dysfunction and associated behavioral dysfunction. Our data highlight the potential relevance of this mechanism in the symptomatic progression in Tauopathies. We furthermore demonstrate that the initial site of Tau-seeding thereby determines the behavioral outcome, potentially underlying the observed heterogeneity in (familial) Tauopathies, including in TauP301 mutants. | - |
dc.description.abstract | Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABA(A)R-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic preformed Tau fibrils in cultured primary neurons. Electrophysiological analysis in organotypic hippocampal slices of Tau transgenic mice demonstrated impaired synaptic transmission and impaired long-term potentiation following Tau-seed induced Tau-aggregation. Intracerebral injection of Tau-seeds in TauP301S mice, caused prion-like spreading of Tau-pathology through functionally connected neuroanatomical pathways. Electrophysiological analysis revealed impaired synaptic plasticity in hippocampal CA1 region 6 months after Tau-seeding in entorhinal cortex (EC). Furthermore, templated Tau aggregation impaired cognitive function, measured in the object recognition test 6 months post-seeding. In contrast, Tau-seeding in basal ganglia and subsequent spreading through functionally connected neuronal networks involved in motor control, resulted in motoric deficits reflected in clasping and impaired inverted grid hanging, not significantly affected following Tau-seeding in EC. Immunostaining, biochemical and electron microscopic analysis in the different models suggested early pathological forms of Tau, including Tau-oligomers, rather than fully mature neurofibrillary tangles (NFTs) as culprits of neuronal dysfunction. We here demonstrate for the first time using in vitro, ex vivo and in vivo models, that prion-like spreading of Tau-misfolding by Tau seeds, along unique neuronal connections, causes neuronal network dysfunction and associated behavioral dysfunction. Our data highlight the potential relevance of this mechanism in the symptomatic progression in Tauopathies. We furthermore demonstrate that the initial site of Tau-seeding thereby determines the behavioral outcome, potentially underlying the observed heterogeneity in (familial) Tauopathies, including in TauP301 mutants. | - |
dc.description.sponsorship | This work was supported by the Belgian Fonds National pour la Recherche Scientifique—Fonds de la Recherche Scientifique (FNRS-FRS; Qualified Researcher, Impulse Financing, Research Credits), by Interuniversity Attraction Poles ProgrammeBelgian State-Belgian Science Policy, The Belgian Fonds de la Recherche Scientifique Médicale, by the Institute for the Promotion of Innovation by Science and Technology (IWT) in Flanders (IWT O&O), Belgium. | - |
dc.language.iso | en | - |
dc.publisher | SPRINGER | - |
dc.rights | The Author(s) 2015. This article is published with open access at Springerlink.com Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | - |
dc.subject.other | AD | - |
dc.subject.other | Tauopathies | - |
dc.subject.other | Tau | - |
dc.subject.other | Prion-like propagation | - |
dc.subject.other | Tau-pathology | - |
dc.subject.other | Neuronal network | - |
dc.subject.other | Synaptic | - |
dc.subject.other | Cognition | - |
dc.subject.other | Motoric deficits | - |
dc.subject.other | TauP301 heterogeneity | - |
dc.subject.other | Animals | - |
dc.subject.other | Animals, Newborn | - |
dc.subject.other | Calcium | - |
dc.subject.other | Cognition Disorders | - |
dc.subject.other | Disease Models, Animal | - |
dc.subject.other | Exploratory Behavior | - |
dc.subject.other | Fura-2 | - |
dc.subject.other | Hippocampus | - |
dc.subject.other | In Vitro Techniques | - |
dc.subject.other | Membrane Potentials | - |
dc.subject.other | Mice | - |
dc.subject.other | Mice, Inbred C57BL | - |
dc.subject.other | Mice, Transgenic | - |
dc.subject.other | Mutation | - |
dc.subject.other | Nerve Net | - |
dc.subject.other | Neurofibrillary Tangles | - |
dc.subject.other | Prions | - |
dc.subject.other | tau Proteins | - |
dc.subject.other | Proteostasis Deficiencies | - |
dc.title | Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice | - |
dc.type | Journal Contribution | - |
dc.identifier.epage | 894 | - |
dc.identifier.issue | 6 | - |
dc.identifier.spage | 875 | - |
dc.identifier.volume | 129 | - |
local.bibliographicCitation.jcat | A1 | - |
local.publisher.place | 233 SPRING ST, NEW YORK, NY 10013 USA | - |
local.type.refereed | Refereed | - |
local.type.specified | Article | - |
local.class | dsPublValOverrule/no_publishing_delay | - |
dc.source.type | Article | - |
dc.identifier.doi | 10.1007/s00401-015-1413-4 | - |
dc.identifier.pmid | 25862635 | - |
dc.identifier.isi | 000354706600008 | - |
dc.identifier.eissn | 1432-0533 | - |
local.provider.type | PubMed | - |
local.uhasselt.uhpub | no | - |
item.fullcitation | STANCU, Ilie Cosmin; Vasconcelos, Bruno; Ris, Laurence; Wang, Peng; Villers, Agnès; PEERAER, Eve; Buist, Arjan; TERWEL, Dick; Baatsen, Peter; Oyelami, Tutu; Pierrot, Nathalie; Casteels, Cindy; Bormans, Guy; Kienlen-Campard, Pascal; Octave, Jean-Nöel; Moechars, Diederik & DEWACHTER, Ilse (2015) Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. In: ACTA NEUROPATHOLOGICA, 129 (6) , p. 875 -894. | - |
item.fulltext | With Fulltext | - |
item.contributor | STANCU, Ilie Cosmin | - |
item.contributor | Vasconcelos, Bruno | - |
item.contributor | Ris, Laurence | - |
item.contributor | Wang, Peng | - |
item.contributor | Villers, Agnès | - |
item.contributor | PEERAER, Eve | - |
item.contributor | Buist, Arjan | - |
item.contributor | TERWEL, Dick | - |
item.contributor | Baatsen, Peter | - |
item.contributor | Oyelami, Tutu | - |
item.contributor | Pierrot, Nathalie | - |
item.contributor | Casteels, Cindy | - |
item.contributor | Bormans, Guy | - |
item.contributor | Kienlen-Campard, Pascal | - |
item.contributor | Octave, Jean-Nöel | - |
item.contributor | Moechars, Diederik | - |
item.contributor | DEWACHTER, Ilse | - |
item.accessRights | Open Access | - |
crisitem.journal.issn | 0001-6322 | - |
crisitem.journal.eissn | 1432-0533 | - |
Appears in Collections: | Research publications |
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Stancu2015_Article_TemplatedMisfoldingOfTauByPrio.pdf | Published version | 4.22 MB | Adobe PDF | View/Open |
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