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Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau

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Neurofibrillary lesions of abnormal Tau are hallmarks of Alzheimer disease and frontotemporal dementias. Our regulatable (Tet-OFF) mouse models of tauopathy express variants of human full-length Tau in the forebrain (CaMKIIα promoter) either with mutation ΔK280 (pro-aggregant) or ΔK280/I277P/I308P (anti-aggregant). Co-expression of luciferase enables in vivo quantification of gene expression by bioluminescence imaging. Pro-aggregant mice develop synapse loss and Tau-pathology including missorting, phosphorylation and early pretangle formation, whereas anti-aggregant mice do not. We correlated hippocampal Tau pathology with learning/memory performance and synaptic plasticity. Pro-aggregant mice at 16 months of gene expression exhibited severe cognitive deficits in Morris water maze and in passive-avoidance paradigms, whereas anti-aggregant mice were comparable to controls. Cognitive impairment of pro-aggregant mice was accompanied by loss of hippocampal LTP in CA1 and CA3 areas and by a reduction of synaptic proteins and dendritic spines, although no neuronal loss was observed. Remarkably, memory and LTP recovered when pro-aggregant Tau was switched-OFF for ~4 months, Tau phosphorylation and missorting were reversed, and synapses recovered. Moreover, soluble and insoluble pro-aggregant hTau40 disappeared, while insoluble mouse Tau was still present. This study links early Tau pathology without neurofibrillary tangles and neuronal death to cognitive decline and synaptic dysfunction. It demonstrates that Tau-induced impairments are reversible after switching-OFF pro-aggregant Tau. Therefore, our mouse model may mimic an early phase of AD when the hippocampus does not yet suffer from irreversible cell death but cognitive deficits are already striking. It offers potential to evaluate drugs with regard to learning and memory performance.

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Human full-length Tau


Calcium/calmodulin-dependent protein kinase IIα


Bioluminescence imaging


Long-term potentiation


Alzheimer disease


Neurofibrillary tangle




Paired helical filament


Frontotemporal dementia


Frontotemporal dementia with parkinsonism linked to chromosome 17


Central nervous system


Tetracycline transactivator


Transgenic mice expressing pro-aggregant full-length hTau40 (12–16 months ON)


Transgenic mice expressing pro-aggregant hTau40, then switched-OFF (8–12 ON + 4 months OFF)


Adenosine triphosphate


Region of interest


Mossy fiber


Neuronal nuclei


Postsynaptic density 95


Glutamate receptor 1


Somatosensory cortex


Morris water maze


Passive avoidance


Paired-pulse facilitation


Paired-pulse ratio


Inter stimulus interval


Theta burst stimulation


Post tetanic potentiation


Field excitatory postsynaptic potential




Frequency facilitation


Α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid


N-methyl d-aspartate


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We thank Dr. A. Haemisch and his team at the animal facility at the University of Hamburg Medical School for their continuous help in mouse breeding, O. Petrova and S. Hahn for their excellent technical assistance, Dr. A. Marx (Max-Planck Unit for Structural Molecular Biology, Hamburg, Germany) for advice on statistics and Dr. G. Glassmeier (University of Hamburg Medical School) for technical advice on electrophysiology. We gratefully acknowledge reagents from Prof. Dr. E. Kandel (Columbia University, New York, NY; CaMKIIα-tTA transgenic mice), Dr. P. Seubert (ElanPharma, South San Francisco, CA; 12E8 antibody) and Dr. P. Davies (Albert Einstein College, Bronx, NY; MC-1 and PHF-1 antibodies). This research was supported by MPG, DZNE, BMBF/KNDD, Wellcome Trust/MRC, Metlife Foundation (to E.M.M.), EU-FP7/Memosad (Grant No. 2006121 to E.M.M. and R. D’H), FWO-Vlaanderen (grant G.0327.08 to D.B. and R. D’H; and an FWO junior scholarship to A.VdJ).

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Correspondence to Eva-Maria Mandelkow.

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A. Van der Jeugd, K. Hochgräfe, T. Ahmed, and J. M. Decker contributed equally.

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Van der Jeugd, A., Hochgräfe, K., Ahmed, T. et al. Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol 123, 787–805 (2012).

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