Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Abstract

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the noncognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~ 6 months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a homecage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12-month of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during nonrapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity. Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau. AbstractModels of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTau P301L+R406W ) knock-in mouse was generated out of the previously characterised PLB1 Triple mouse, and named PLB2 Tau . After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which was coincided with the emergence of FTD relevant behavioural traits. In...

Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

“…Overall, our data lend direct support to the patho-physiological relevance of non-filamentous, oligomeric tau. Nevertheless, strong correlations with cognitive decline were also observed for conformational and phospho-tau as previously reported in humans [25, 30] and animal models [43, 44, 83]. Our data expand on the suggested disruptive role of monomeric phospho-tau [41], and suggest oligomerization caused by pathological modification of monomeric tau to play a key role.…”

Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model

“…The amygdala is involved in creating, maintaining and modifying anxiety and fear responses. Furthermore, increased anxiety is commonly observed in patients with Alzheimer’s disease or frontotemporal lobar degeneration (FTLD) (Porter et al , 2003), and increased anxiety-like behaviour has been found in FTLD-Tau mouse models, as assessed by the elevated plus maze (Walf and Frye, 2007; Koss et al , 2016). Age-matched pR5 mice were split into four treatment groups (Fig.…”

“…Anxiety-like behaviour was assessed by the elevated plus maze as previously described (Koss et al , 2016) with some changes. Briefly, mice were placed in the central area of the maze (elevated cross-shaped apparatus with a central square, and closed as well as open arms with unprotected edges).…”

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

“…Second, tTA/WT12 mice display early deficits in cognitive function, most remarkably impaired working memory, a frontal cortex-dependent function. They also show signs of a mild decrease in anxiety in the elevated plus maze test, which some authors interpret as disinhibition and might indicate alterations in amygdala or prefrontal cortex function (Roberson, 2012; Koss et al, 2016). These phenotypes are consistent with those observed in other FTD mouse models (Takeuchi et al, 2011; Przybyla et al, 2016; Vernay et al, 2016a), although in some FTD models an increase in anxiety was also reported (Koss et al, 2016; Liu et al, 2016).…”

“…In this context, our behavioral data from tTA/WT12 mice constitutes further evidence for a link between TDP-43 dysregulation and sociability. A forebrain specific, human mutated Tau (hTauP301L + R406W) knock-in mouse showed FTD-relevant phenotypes related to semantic memory, anxiety, anhedonia, sleep and activity (Koss et al, 2016), and mice expressing human P301S mutant tau protein recapitulated neurological deficits of human tauopathies, including early abnormalities in the open field test, the elevated plus-maze test, Y-maze test, Barnes maze test and the Morris water maze test (Takeuchi et al, 2011). Importantly, most of these studies were performed when motor deficits were not preeminent, although in some cases detailed characterization was not reported, in contrast to the current analysis of tTA/WT12 mice.…”