TY  - JOUR
AU  - Decker, Jochen Martin
AU  - Krüger, Lars
AU  - Sydow, Astrid
AU  - Dennissen, Frank Ja
AU  - Siskova, Zuzana
AU  - Mandelkow, Eckhard
AU  - Mandelkow, Eva-Maria
TI  - The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity.
JO  - EMBO reports
VL  - 17
IS  - 4
SN  - 1469-221X
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-04807
SP  - 552-569
PY  - 2016
AB  - 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.
KW  - Animals
KW  - CA3 Region, Hippocampal: metabolism
KW  - CA3 Region, Hippocampal: pathology
KW  - Calcium: metabolism
KW  - Culture Media: chemistry
KW  - Disease Models, Animal
KW  - Frontotemporal Dementia: physiopathology
KW  - Glutamic Acid: analysis
KW  - Humans
KW  - Mice
KW  - Mice, Transgenic
KW  - Mutation
KW  - Neuronal Plasticity
KW  - Neurons: chemistry
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Organ Culture Techniques
KW  - Receptors, N-Methyl-D-Aspartate: metabolism
KW  - Synaptic Transmission
KW  - tau Proteins: chemistry
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - Culture Media (NLM Chemicals)
KW  - NR2B NMDA receptor (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Glutamic Acid (NLM Chemicals)
KW  - Calcium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26931569
C2  - pmc:PMC4818782
DO  - DOI:10.15252/embr.201541439
UR  - https://pub.dzne.de/record/138485
ER  -