title: Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant.
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 Tau(RD) 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 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.
authors.affiliation: Max Planck Unit for Structural Molecular Biology, c/o DESY, 22607 Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Sydow
authors.forename: Ann
authors.initials: A
authors.lastname: Van der Jeugd
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmed
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
authors.forename: Olga
authors.initials: O
authors.lastname: Petrova
authors.forename: Dagmar
authors.initials: D
authors.lastname: Drexler
authors.forename: Lepu
authors.initials: L
authors.lastname: Zhou
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rune
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D018737:Hand Strength / Q000502:physiology; D006624:Hippocampus / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009483:Neuropsychological Tests; D017434:Protein Structure, Tertiary; D013028:Space Perception / Q000502:physiology; D013569:Synapses / Q000473:pathology / Q000648:ultrastructure; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D016875:tau Proteins; D004318:Doxycycline