Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model

Astrid Sydow, Ann Van Der Jeugd, Fang Zheng, Tariq Ahmed, Detlef Balschun, Olga Petrova, Dagmar Drexler, Lepu Zhou, Gabriele Rune, Eckhard Mandelkow, Rudi D'Hooge, Christian Alzheimer, Eva Maria Mandelkow

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 (Tau RD) 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" Tau RD 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 Tau RD mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau RD, 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 Tau RD species rather than by mouse Tau aggregates.

Original languageEnglish
Pages (from-to)432-437
Number of pages6
JournalJournal of Molecular Neuroscience
Volume45
Issue number3
DOIs
Publication statusPublished - 1 Nov 2011

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Keywords

  • Aggregation
  • Frontotemporal dementia
  • Tau
  • Tauopathy
  • Transgenic mouse models

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Sydow, A., Van Der Jeugd, A., Zheng, F., Ahmed, T., Balschun, D., Petrova, O., Drexler, D., Zhou, L., Rune, G., Mandelkow, E., D'Hooge, R., Alzheimer, C., & Mandelkow, E. M. (2011). Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model. Journal of Molecular Neuroscience, 45(3), 432-437. https://doi.org/10.1007/s12031-011-9604-5