Abstract
The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (TauRD) carrying the FTDP-17 mutation ΔK280 in a “pro-aggregant” and an “anti-aggregant” version. Based on the enhanced tendency of Tau to aggregate, only the “pro-aggregant” TauRD mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant TauRD mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human TauRD, memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human TauRD species rather than by mouse Tau aggregates.
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Abbreviations
- AD:
-
Alzheimer’s disease
- CBD:
-
Corticobasal degeneration
- DOX:
-
Doxycycline
- EPSP:
-
Excitatory postsynaptic potential
- FTD:
-
Frontotemporal dementia
- FTDP-17:
-
Frontotemporal dementia with Parkinsonism linked to chromosome 17
- LTP:
-
Long-term potentiation
- MARK:
-
Microtubule affinity regulating kinase
- Mf:
-
mossy fiber
- NFTs:
-
Neurofibrillary tangles
- NMDAR:
-
NMDA receptor
- PHFs:
-
Paired helical filaments
- PiD:
-
Pick's disease
- PSP:
-
Progressive supranuclear palsy
- TauRD :
-
Repeat domain of human Tau
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Acknowledgments
We thank Dr. A. Haemisch and his team of the animal facility at University of Hamburg Medical School for their continuous help in mouse breeding, Dr. H. Bujard and K. Schoenig (University of Heidelberg) for initial help with inducible transgenic mice, S. Hahn and A. Hofmann for excellent technical assistance, and Dr. A. Marx (Hamburg) for advice on statistics. We gratefully acknowledge reagents from Dr. E. Kandel (Columbia University, New York—CaMKIIα-tTA activator transgenic mice). This research was supported by the Max-Planck-Society, Deutsche Forschungsgemeinschaft (AL 294/9-1 to C.A.), the Bundesministerium für Bildung und Forschung/Kompetenznetz Degenerative Demenzen program (E.-M.M.), the Breuer Foundation (E.-M.M.), EU-FP7/Memosad (Grant Agreement 2006121 to E.-M.M. and R.D.), Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen (Grant G.0327.08 to D.B. and R.D., FWOjunior scholarship to A.V.d.J.), the KUL2004 Impulse Program, Interdisciplinair Onderzoek Project 06/004, Onderzoekstoelage 06/23 (D.B.), and a K.U. Leuven fellowship (T.A.).
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Sydow, A., Van der Jeugd, A., Zheng, F. et al. Reversibility of Tau-Related Cognitive Defects in a Regulatable FTD Mouse Model. J Mol Neurosci 45, 432–437 (2011). https://doi.org/10.1007/s12031-011-9604-5
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DOI: https://doi.org/10.1007/s12031-011-9604-5