Cited by 302Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Sydow, Astrid, Van der Jeugd, Ann, Zheng, Fang, Ahmed, Tariq, Balschun, Detlef, Petrova, Olga, Drexler, Dagmar, Zhou, Lepu +5 more·2011·The Journal of Neuroscience

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.

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Crossref · 10.1523/jneurosci.5245-10.2011

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  • Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.

    “Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
  • Deficiencies in SIRT1 are correlated with enhanced levels of phosphorylated tau in neurons and the number of neurofibrillary tangles in the brains of AD subjects.

    “Consequently, deficiencies in SIRT1 have also been correlated with enhanced levels of phosphorylated tau in the neurons and the number of neurofibrillary tangles in the brains of AD subjects [171,172].”

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Authors
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.
Affiliations
  • Deutsches Elektronen-Synchrotron DESY (DE)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • KU Leuven (BE)
  • Max Planck Unit for Structural Molecular Biology (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • German Center for Neurodegenerative Diseases (DE)
Venue
The Journal of Neuroscience
Published
2011-02-16
Volume
31
Issue
7
Pages
2511-2525
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1970686195
Cited by
302
References
91
Citations by year
2026: 10 · 2025: 15 · 2024: 15 · 2023: 13 · 2022: 21 · 2021: 20 · 2020: 19 · 2019: 21 · 2018: 18 · 2017: 25 · 2016: 19 · 2015: 18 · 2014: 21 · 2013: 20 · 2012: 30
FWCI
19.20
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • DZNE Pub (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (AL 294/9-1)
  • Fonds Wetenschappelijk Onderzoek
  • Max-Planck-Gesellschaft
  • Vlaamse regering
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tau protein, tau repeat domain, tau aggregation, Alzheimer's disease, long-term potentiation, synaptic plasticity, learning and memory, reversible neurotoxicity, transgenic mice, neuronal loss, memory impairment
MeSH terms
Animals, Disease Models, Animal, Doxycycline, Hippocampus, Humans, Memory, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Neuropsychological Tests, Space Perception, Synapses, Time Factors, tau Proteins, Protein Structure, Tertiary, Long-Term Potentiation, Hand Strength, Maze Learning, Tauopathies, Mice, In Vitro Techniques

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