title: Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau.
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.
authors.affiliation: Laboratory of Biological Psychology, Dept. Psychology, K.U.Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Van der Jeugd
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases) and CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hochgräfe
authors.affiliation: Laboratory of Biological Psychology, Dept. Psychology, K.U.Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmed
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases) and CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Jochen M
authors.initials: JM
authors.lastname: Decker
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleuelerstr. 50, 50931 Cologne, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Sydow
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleuelerstr. 50, 50931 Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases) and CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|Max-Planck-Institute for Neurological Research, Gleuelerstr. 50, 50931 Cologne, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases) and CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Messing
authors.affiliation: Laboratory of Biological Psychology, Dept. Psychology, K.U.Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
authors.affiliation: Laboratory of Biological Psychology, Dept. Psychology, K.U.Leuven, Tiensestraat 102, 3000 Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases) and CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|Max-Planck-Institute for Neurological Research, Gleuelerstr. 50, 50931 Cologne, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D013569:Synapses / Q000235:genetics / Q000473:pathology; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins