Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant.
Standard
Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. / Sydow, Astrid; Ann, Van der Jeugd; Zheng, Fang; Ahmed, Tariq; Balschun, Detlef; Petrova, Olga; Drexler, Dagmar; Zhou, Lepu; Rune, Gabriele M.; Mandelkow, Eckhard; Alzheimer, Christian; Mandelkow, Eva-Maria.
In: J NEUROSCI, Vol. 31, No. 7, 7, 2011, p. 2511-2525.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant.
AU - Sydow, Astrid
AU - Ann, Van der Jeugd
AU - Zheng, Fang
AU - Ahmed, Tariq
AU - Balschun, Detlef
AU - Petrova, Olga
AU - Drexler, Dagmar
AU - Zhou, Lepu
AU - Rune, Gabriele M.
AU - Mandelkow, Eckhard
AU - Alzheimer, Christian
AU - Mandelkow, Eva-Maria
PY - 2011
Y1 - 2011
N2 - 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 Tau(RD) in two forms, differing in their propensity for ?-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 ?-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 Tau(RD) 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 ? 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. 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.
AB - 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 Tau(RD) in two forms, differing in their propensity for ?-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 ?-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 Tau(RD) 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 ? 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. 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.
M3 - SCORING: Journal article
VL - 31
SP - 2511
EP - 2525
JO - J NEUROSCI
JF - J NEUROSCI
SN - 0270-6474
IS - 7
M1 - 7
ER -