Title: Tau-Induced Defects in Synaptic Plasticity, Learning, and Memory Are Reversible in Transgenic Mice after Switching Off the Toxic Tau Mutant
Authors: Sydow, Astrid *
Van der Jeugd, Anneke *
Zheng, Fang
Ahmed, Tariq
Balschun, Detlef
Petrova, Olga
Drexler, Dagmar
Zhou, Lepu
Rune, Gabriele
Mandelkow, Eckhard
D'Hooge, Rudi
Alzheimer, Christian
Mandelkow, Eva-Maria # ×
Issue Date: 16-Feb-2011
Publisher: The Society for Neuroscience
Series Title: Journal of Neuroscience vol:31 issue:7 pages:2511-2525
Abstract: This report describes the behavioral and electrophysiological analysis of regulatable transgenic mice expressing mutant repeat domains of human Tau (Tau(RD)). Mice were generated to express TauRD in two forms, differing in their propensity for beta-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 beta-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 Tau(RD) 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 Tau(RD) is switched on for similar to 10 months and off for similar to 4 months, memory and LTP recover, whereas aggregates decrease moderately and change their composition from mixed human plus mouse Tau to mouse Tau only. Neuronal loss persists, but synapses are partially rescued. This argues that continuous presence of amyloidogenic pro-aggregant Tau(RD) constitutes the main toxic insult for memory and LTP, rather than the aggregates as such.
ISSN: 0270-6474
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Biological Psychology
* (joint) first author
× corresponding author
# (joint) last author

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