title: Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice.
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.
authors: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors: Ilie-Cosmin
authors: IC
authors: Stancu
authors: Bruno
authors: B
authors: Vasconcelos
authors: Laurence
authors: L
authors: Ris
authors: Peng
authors: P
authors: Wang
authors: Agnès
authors: A
authors: Villers
authors: Eve
authors: E
authors: Peeraer
authors: Arjan
authors: A
authors: Buist
authors: Dick
authors: D
authors: Terwel
authors: Peter
authors: P
authors: Baatsen
authors: Tutu
authors: T
authors: Oyelami
authors: Nathalie
authors: N
authors: Pierrot
authors: Cindy
authors: C
authors: Casteels
authors: Guy
authors: G
authors: Bormans
authors: Pascal
authors: P
authors: Kienlen-Campard
authors: Jean-Nöel
authors: JN
authors: Octave
authors: Diederik
authors: D
authors: Moechars
authors: Ilse
authors: I
authors: Dewachter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D016257:Fura-2 / Q000031:analogs & derivatives / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009415:Nerve Net / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011328:Prions / Q000378:metabolism*; D057165:Proteostasis Deficiencies; D024801:Tauopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D011328:Prions; D016875:tau Proteins; C049925:fura-2-am; D002118:Calcium; D016257:Fura-2