Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic tau mutant

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

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Abstract

This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (TauRD). Mice were generated to express TauRD in two forms, differing in their propensity for β-structure and thus in their tendency for aggregation ("pro-aggregant" or "anti- aggregant") (Mocanu et al., 2008). Only pro-aggregant mice show pronounced changes typical for Tau pathology in Alzheimer's disease (aggregation, missorting, hyperphosphorylation, synaptic and neuronal loss), indicating that the β-propensity and hence the ability to aggregate is a key factor in the disease. We now tested the mice with regard to neuromotor parameters, behavior, learning and memory, and synaptic plasticity and correlated this with histological and biochemical parameters in different stages of switching TauRD on or off. The mice are normal in neuromotor tests. However, pro-aggregant TauRD mice are strongly impaired in memory and show pronounced loss of long-term potentiation (LTP), suggesting that Tau aggregation specifically perturbs these brain functions. Remarkably, when the expression of human pro-aggregant TauRD is switched on for ∼10 months and off for ∼4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuron al loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant TauRD constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.

Original languageEnglish
Pages (from-to)2511-2525
Number of pages15
JournalJournal of Neuroscience
Volume31
Issue number7
DOIs
Publication statusPublished - 16 Feb 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Neuroscience(all)

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). Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic tau mutant. Journal of Neuroscience, 31(7), 2511-2525. https://doi.org/10.1523/JNEUROSCI.5245-10.2011