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

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Abstract

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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Abbreviations

hTau40:

Human full-length Tau

CaMKIIα:

Calcium/calmodulin-dependent protein kinase IIα

BLI:

Bioluminescence imaging

LTP:

Long-term potentiation

AD:

Alzheimer disease

NFT:

Neurofibrillary tangle

MT:

Microtubule

PHF:

Paired helical filament

FTD:

Frontotemporal dementia

FTDP-17:

Frontotemporal dementia with parkinsonism linked to chromosome 17

CNS:

Central nervous system

tTA:

Tetracycline transactivator

pro-ON:

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

pro-ON/OFF:

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

ATP:

Adenosine triphosphate

ROI:

Region of interest

Mf:

Mossy fiber

NeuN:

Neuronal nuclei

PSD95:

Postsynaptic density 95

GluR1:

Glutamate receptor 1

SSCx:

Somatosensory cortex

MWM:

Morris water maze

PA:

Passive avoidance

PPF:

Paired-pulse facilitation

PPR:

Paired-pulse ratio

ISI:

Inter stimulus interval

TBS:

Theta burst stimulation

PTP:

Post tetanic potentiation

fEPSP:

Field excitatory postsynaptic potential

I/O:

Input/output

Ff:

Frequency facilitation

AMPA:

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

NMDA:

N-methyl d-aspartate

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Acknowledgments

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).

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

  1. Katja Hochgräfe, Astrid Sydow & Anne Hofmann

    Present address: Max-Planck-Unit for Structural Molecular Biology, c/o Desy, Notkestr. 85, 22607, Hamburg, Germany

Authors and Affiliations

  1. DZNE (German Center for Neurodegenerative Diseases) and CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany

    Katja Hochgräfe, Jochen M. Decker, Dan Wu, Lars Messing & Eva-Maria Mandelkow

  2. Laboratory of Biological Psychology, Department of Psychology, K.U.Leuven, Tiensestraat 102, 3000, Leuven, Belgium

    Ann Van der Jeugd, Tariq Ahmed, Detlef Balschun & Rudi D’Hooge

  3. Max-Planck-Institute for Neurological Research, Gleuelerstr. 50, 50931, Cologne, Germany

    Astrid Sydow, Anne Hofmann, Dan Wu & Eva-Maria Mandelkow

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Corresponding author

Correspondence to Eva-Maria Mandelkow.

Additional information

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). https://doi.org/10.1007/s00401-012-0987-3

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  • DOI: https://doi.org/10.1007/s00401-012-0987-3

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