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 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1413-4) contains supplementary material, which is available to authorized users.

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

“…In vivo studies of prion-like induction of tauopathy have utilized intracerebral injection of brain lysate from tau transgenic mice or human tauopathy into P301L or P301S human tau transgenic mouse models (61-63), as well as the ALZ17 WT human tau mouse line, which has been reported to show inclusions following brain lysate from tauopathy mice or human cases, but this is a slower process (32,33). Studies using recombinant fibrillar tau for direct intracerebral seeding demonstrated the induction of tau pathology in transgenic mice expressing either P301L or P301S human tau, but not in transgenic mice expressing WT human tau (34,35,64,65). However, it is likely that tau aggregates within brain lysate have higher seeding potencies than recombinant tau fibrils (54).…”

Widespread tau seeding activity at early Braak stages

“…In recent years, numerous mouse studies have demonstrated that tau aggregates inoculated into the brain trigger spreading tau pathology [2, 12, 13, 23, 25, 27, 31, 36]. Further, we previously observed a steady increase in tau seeding activity in the PS19 tauopathy mouse brain, even in the absence of seed inoculation [21, 39].…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…Moreover, recent studies have shown that propagation and seeding of Aβ, tau, and α-syn in a prion-like manner might also contribute to neurodegeneration [22][23][24][25][26][27][28]. Remarkably, there is also evidence that these various protein aggregates can interact with each other [29].…”