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Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice.

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Stancu, Ilie-Cosmin [UCL] Barbosa de Vasconcelos, Bruno [UCL] Ris, Laurence Wang, Peng [UCL] Villers, Agnès Pierrot, Nathalie [UCL] Kienlen-Campard, Pascal [UCL] Octave, Jean-Noël [UCL] Dewachter, Ilse [UCL]

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 GABAAR-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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2015
Language Anglais
Journal information "Acta Neuropathologica" - Vol. 129, no.6, p. 875-894 (2015)
Peer reviewed yes
Publisher Springer (Heidelberg)
issn 0001-6322
e-issn 1432-0533
Publication status Publié
Affiliation UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire
Links
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Bibliographic reference Stancu, Ilie-Cosmin ; Barbosa de Vasconcelos, Bruno ; Ris, Laurence ; Wang, Peng ; Villers, Agnès ; et. al. 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, Vol. 129, no.6, p. 875-894 (2015)
Permanent URL http://hdl.handle.net/2078.1/161697