title: The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity.
abstract: We report on a novel transgenic mouse model expressing human full-length Tau with the Tau mutation A152T (hTau(AT)), a risk factor for FTD-spectrum disorders including PSP and CBD Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis-sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short- or long-term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage-gated sodium channels. CA3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1. In summary, hTau(AT) causes excitotoxicity mediated by NR2B-containing NMDA receptors due to enhanced extracellular glutamate.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Jochen Martin
authors.initials: JM
authors.lastname: Decker
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Krüger
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Max-Planck-Institute for Metabolism Research (Cologne), Hamburg Outstation, Hamburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Sydow
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Frank Ja
authors.initials: FJ
authors.lastname: Dennissen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Siskova
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Max-Planck-Institute for Metabolism Research (Cologne), Hamburg Outstation, Hamburg, Germany Caesar Research Center, Bonn, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany Max-Planck-Institute for Metabolism Research (Cologne), Hamburg Outstation, Hamburg, Germany Caesar Research Center, Bonn, Germany eva.mandelkow@dzne.de.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000503:physiopathology*; D018698:Glutamic Acid / Q000032:analysis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009473:Neuronal Plasticity; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D003470:Culture Media; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D018698:Glutamic Acid; D002118:Calcium
keywords: CA3; NR2B; Tau; excitotoxicity; frontotemporal‐spectrum disorders