Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice
| Autor: | Dick Terwel, Tutu Oyelami, Diederik Moechars, Jean-Noël Octave, Ilse Dewachter, Agnès Villers, Guy Bormans, Ilie-Cosmin Stancu, Arjan Buist, Peng Wang, Peter Baatsen, Nathalie Pierrot, Eve Peeraer, Laurence Ris, Cindy Casteels, Bruno Barbosa de Vasconcelos, Pascal Kienlen-Campard |
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| Přispěvatelé: | 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 |
| Jazyk: | angličtina |
| Předmět: |
Pathology
Nerve net Neuronal network Hippocampus Hippocampal formation Membrane Potentials Mice Cognition Motoric deficits Synaptic Tau-pathology Neurofibrillary Tangles Long-term potentiation medicine.anatomical_structure Tauopathies Prion-like propagation Fura-2 medicine.medical_specialty Prions Clinical Neurology Mice Transgenic tau Proteins In Vitro Techniques Neurotransmission Biology Pathology and Forensic Medicine Cellular and Molecular Neuroscience TauP301 heterogeneity mental disorders medicine Biological neural network Animals Proteostasis Deficiencies Original Paper AD Entorhinal cortex Mice Inbred C57BL Disease Models Animal Animals Newborn nervous system Mutation Synaptic plasticity Exploratory Behavior Calcium Neurology (clinical) Tau Nerve Net Cognition Disorders Neuroscience |
| Zdroj: | Article Acta Neuropathologica |
| ISSN: | 0001-6322 |
| DOI: | 10.1007/s00401-015-1413-4 |
| Popis: | 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. 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. 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. |
| Databáze: | OpenAIRE |
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