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Journal Article

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


Mandelkow,  E. M.
Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society;

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Van der Jeugd, A., Hochgrafe, K., Ahmed, T., Decker, J. M., Sydow, A., Hofmann, A., et al. (2012). Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathologica, 123(6), 787-805. doi:DOI 10.1007/s00401-012-0987-3.

Cite as: http://hdl.handle.net/11858/00-001M-0000-0028-62A5-C
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 (CaMKII alpha promoter) either with mutation Delta K280 (pro-aggregant) or Delta K280/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 similar to 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.