Cited by 135Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau

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Van der Jeugd, Ann, Hochgräfe, Katja, Ahmed, Tariq, Decker, Jochen M., Sydow, Astrid, Hofmann, Anne, Wu, Dan, Messing, Lars +3 more·2012·Acta Neuropathologica

Abstract

Neurofibrillary lesions of abnormal Tau are hallmarks of Alzheimer disease and frontotemporal dementias. Our regulatable (Tet-OFF) mouse models of tauopathy express variants of human full-length Tau in the forebrain (CaMKIIα promoter) either with mutation ΔK280 (pro-aggregant) or ΔK280/I277P/I308P (anti-aggregant). Co-expression of luciferase enables in vivo quantification of gene expression by bioluminescence imaging. Pro-aggregant mice develop synapse loss and Tau-pathology including missorting, phosphorylation and early pretangle formation, whereas anti-aggregant mice do not. We correlated hippocampal Tau pathology with learning/memory performance and synaptic plasticity. Pro-aggregant mice at 16 months of gene expression exhibited severe cognitive deficits in Morris water maze and in passive-avoidance paradigms, whereas anti-aggregant mice were comparable to controls. Cognitive impairment of pro-aggregant mice was accompanied by loss of hippocampal LTP in CA1 and CA3 areas and by a reduction of synaptic proteins and dendritic spines, although no neuronal loss was observed. Remarkably, memory and LTP recovered when pro-aggregant Tau was switched-OFF for ~4 months, Tau phosphorylation and missorting were reversed, and synapses recovered. Moreover, soluble and insoluble pro-aggregant hTau40 disappeared, while insoluble mouse Tau was still present. This study links early Tau pathology without neurofibrillary tangles and neuronal death to cognitive decline and synaptic dysfunction. It demonstrates that Tau-induced impairments are reversible after switching-OFF pro-aggregant Tau. Therefore, our mouse model may mimic an early phase of AD when the hippocampus does not yet suffer from irreversible cell death but cognitive deficits are already striking. It offers potential to evaluate drugs with regard to learning and memory performance.

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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].”

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Authors
Van der Jeugd, A., Hochgräfe, K., Ahmed, T., Decker, J. M., Sydow, A., Hofmann, A., Wu, D., Messing, L., Balschun, D., D’Hooge, R., & Mandelkow, E.-M.
Affiliations
  • Center of Advanced European Studies and Research (DE)
  • KU Leuven (BE)
  • Max Planck Society (DE)
Corresponding author
Mandelkow, Eva-Maria
Venue
Acta Neuropathologica
Published
2012-04-25
Volume
123
Issue
6
Pages
787-805
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
OpenAlex
W2030674642
Cited by
135
References
83
Citations by year
2026: 2 · 2025: 11 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 13 · 2019: 6 · 2018: 6 · 2017: 10 · 2016: 12 · 2015: 19 · 2014: 9 · 2013: 13 · 2012: 3
FWCI
9.43
Type
journal article
Language
en
Open access
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • Max Planck Digital Library (submittedVersion)
  • Lirias (submittedVersion)
  • DZNE Pub (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • Wellcome Trust (089703)
  • Medical Research Council (MC_G1000734)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tauopathy, Alzheimer's disease, frontotemporal dementia, cognitive impairment, hippocampal long-term potentiation, synaptic plasticity, synaptic loss, dendritic spines, tau phosphorylation, learning and memory, bioluminescence imaging
MeSH terms
Alzheimer Disease, Animals, Cognition Disorders, Disease Models, Animal, Hippocampus, Humans, Learning, Mice, Transgenic, Neuropsychological Tests, Synapses, Time Factors, Gene Expression, Neurofibrillary Tangles, tau Proteins, Long-Term Potentiation, Tauopathies, Mice

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