Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD

Abstract

IntroductionMutations of Tau are associated with several neurodegenerative disorders. Recently, the Tau mutation A152T was described as a novel risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease. In vitro Tau-A152T shows a decreased binding to microtubules and a reduced tendency to form abnormal fibers.ResultsTo study the effects of this mutation we generated a mouse model expressing human full-length Tau with this mutation (hTau40AT). At young age (2–3 months) immunohistological analysis reveals pathological Tau conformation and Tau-hyperphosphorylation combined with Tau missorting into the somatodendritic compartment of neurons. With increasing age there is Tau aggregation including co-aggregates of endogenous mouse Tau and exogenous human Tau, accompanied by loss of synapses (especially presynaptic failure) and neurons. From ~10 months onwards the mice show a prominent neuroinflammatory response as judged by activation of microglia and astrocytes. This progressive neuroinflammation becomes visible by in vivo bioluminescence imaging after crossbreeding of hTau40AT mice and Gfap-luciferase reporter mice. In contrast to other Tau-transgenic models and Alzheimer disease patients with reduced protein clearance, hTau40AT mice show a strong induction of autophagy. Although Tau-hyperphosphorylation and aggregation is also present in spinal cord and motor cortex (due to the Thy1.2 promoter), neuromotor performance is not affected. Deficits in spatial reference memory are manifest at ~16 months and are accompanied by neuronal death.ConclusionsThe hTau40AT mice mimic pathological hallmarks of tauopathies including a cognitive phenotype combined with pronounced neuroinflammation visible by bioluminescence. Thus the mice are suitable for mechanistic studies of Tau induced toxicity and in vivo validation of neuroprotective compounds.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0281-z) contains supplementary material, which is available to authorized users.

Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

“…Collectively, these results suggest that an early marker of A152T pathogenesis is an early and time-dependent accumulation of tau, predominantly in the form of P-tau and oligomeric P-tau. IF corroborated the accumulation of tau/P-tau in A152T neurons, further revealing increased P-tau in neuronal processes and cell body of A152T neurons, consistent with somatodendritic redistribution, both important pathophysiological features of tauopathy, detected here as an early phenotype in patient-derived neurons in vitro ( de Calignon et al., 2012 , Fong et al., 2013 , Li et al., 2011 , Sydow et al., 2016 ).…”

“…We took advantage of this system to investigate the early events of tau-A152T pathology that may be causal in FTD. Our findings contribute to mounting evidence, across studies of different tau mutations and across model systems, of tau-mediated molecular events associated with neurodegeneration, toward the identification of relevant therapeutic targets ( Ehrlich et al., 2015 , Fong et al., 2013 , Iovino et al., 2015 , Maeda et al., 2016 , Decker et al., 2016 , Pir et al., 2016 , Sydow et al., 2016 , Wren et al., 2015 ). We biochemically profiled neurons derived from control and A152T carriers, and report on a phenotyping platform for tau regarding protein levels, PTMs, and solubility.…”

“…Here, we investigated the underlying molecular and cellular mechanisms of pathogenicity associated with the rare tau variant A152T in a human neuronal context. Although the role of tau A152T in disease is still debated, it has been shown to affect tau function and PTMs, promote oligomerization and postmortem detection of inclusions, cause neuronal dysfunction independent of aggregation and neuroinflammation in animal models, and increase significantly the risk for FTD and other neurodegenerative diseases ( Coppola et al., 2012 , Kara et al., 2012 , Labbe et al., 2015 , Lee et al., 2013 , Maeda et al., 2016 , Decker et al., 2016 , Pir et al., 2016 , Sydow et al., 2016 ). We utilized iPSCs derived from A152T carriers and derived neural progenitor cells (NPCs) and differentiated neuronal cells ( Figure 1 A).…”

Interplay of pathogenic forms of human tau with different autophagic pathways

“…By contrast, the A152T mutation lies far outside the repeat domain and has only a weak effect on tau aggregation, and its role as a risk factor in FTD spectrum disorders or AD is still poorly understood. The different effects of both mutations have been further demonstrated by comparing the phenotype of P301L (Lin et al ., 2003) and the novel tau‐A152T transgenic mouse models (Decker et al ., 2016; Maeda et al ., 2016; Sydow et al ., 2016). However, the basis for these phenotypic differences is not fully understood.…”

“…S6, Supporting information). The different impact of both mutations in the autophagic degradation of tau goes in line with the severity of tau toxicity in the mouse models expressing copies of these proteins (Lin et al ., 2003; Decker et al ., 2016; Maeda et al ., 2016; Sydow et al ., 2016). Pathology and tau aggregation in mouse expressing the Tau‐A152T mutation occur at a slower pace than in the tau‐P301L overexpressor, where tangles appear as early as 4.5 month (Lin et al ., 2003) and where we found a more severe impairment of its autophagic degradation.…”