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

Ann Van Der Jeugd, Katja Hochgräfe, Tariq Ahmed, Jochen M. Decker, Astrid Sydow, Anne Hofmann, Dan Wu, Lars Messing, Detlef Balschun, Rudi D'Hooge, Eva Maria Mandelkow

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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. Proaggregant 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 proaggregant 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.

Original languageEnglish
Pages (from-to)787-805
Number of pages19
JournalActa Neuropathologica
Volume123
Issue number6
DOIs
Publication statusPublished - 1 Jun 2012

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Keywords

  • Alzheimer disease
  • Behavior
  • Bioluminescene imaging
  • Long-term potentiation
  • Tau mouse model

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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. (2012). Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathologica, 123(6), 787-805. https://doi.org/10.1007/s00401-012-0987-3