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.
Highlights
Mutations of Tau are associated with several neurodegenerative disorders
Generation of hTau40AT mice To mimic pathological hallmarks of genetically provoked tauopathies, we created a novel transgenic mouse model expressing human full-length Tau (441aa, 2N4R) with the mutation A152T, which has been linked to frontotemporal dementias (FTD) spectrum disorders such as progressive supranuclear palsy (PSP) [20] (Fig. 1a)
Scheme represents human full-length Tau with highlighted A152T mutation, proline-rich domain, N-terminal inserts and aggregation-prone hexapeptide motifs (PHF6*, PHF6) in the repeat domain. hTau40AT -expression is controlled by the murine Thy1.2 promoter. b Representative expression of hTau40AT (Mr ~67 kDa) and endogenous mouse Tau (Mr ~ 45-55 kDa) in cortex, hippocampus, spinal cord and cerebellum of 2 months old hTau40AT mice and age matched controls (WT) detected by the pan-Tau antibody K9JA
Summary
The Tau mutation A152T was described as a novel risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease. Tauopathies define a class of neurodegenerative diseases associated with the pathological deposition of Tau protein in different substructures of the human brain. Major risk factors for FTDs are mutations within the microtubule associated protein Tau (MAPT) gene located on chromosome 17 (17q21) [4]. Most MAPT mutations are clustered in exons 9–13, encoding for the Tau repeat domain and flanking regions responsible for microtubule (MT) binding. These Tau mutations destabilize microtubules and enhance Tauaggregation since the β-sheet rich repeat domain plays a major role in Tau filament assembly [70]
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