Journal Article

DZNE-2020-04807

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity.

Decker, J. M. (First author)DZNE* ; Krüger, L.DZNE* ; Sydow, A.DZNE* ; Dennissen, F. J.DZNE* ; Siskova, Z.DZNE* ; Mandelkow, E.DZNE* ; Mandelkow, E.-M. (Last author)DZNE*

2016
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embr.201541439

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.

Keyword(s): Animals (MeSH) ; CA3 Region, Hippocampal: metabolism (MeSH) ; CA3 Region, Hippocampal: pathology (MeSH) ; Calcium: metabolism (MeSH) ; Culture Media: chemistry (MeSH) ; Disease Models, Animal (MeSH) ; Frontotemporal Dementia: physiopathology (MeSH) ; Glutamic Acid: analysis (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Mutation (MeSH) ; Neuronal Plasticity (MeSH) ; Neurons: chemistry (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Organ Culture Techniques (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Synaptic Transmission (MeSH) ; tau Proteins: chemistry (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Culture Media ; NR2B NMDA receptor ; Receptors, N-Methyl-D-Aspartate ; tau Proteins ; Glutamic Acid ; Calcium

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Contributing Institute(s):

1. Cell and Animal Models of Neurodegeneration (AG (Eva) Mandelkow)
2. Neuronal Networks (AG Remy)
3. Technology Transfer and Industry Collaborations Unit (Tech Transfer)
4. Structural Principles of Neurodegeneration (AG (Eckhard) Mandelkow)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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