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000138485 1001_ $$0P:(DE-2719)2810343$$aDecker, Jochen Martin$$b0$$eFirst author$$udzne
000138485 245__ $$aThe Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity.
000138485 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2016
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000138485 520__ $$aWe 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.
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000138485 650_7 $$2NLM Chemicals$$aCulture Media
000138485 650_7 $$2NLM Chemicals$$aNR2B NMDA receptor
000138485 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000138485 650_7 $$2NLM Chemicals$$atau Proteins
000138485 650_7 $$03KX376GY7L$$2NLM Chemicals$$aGlutamic Acid
000138485 650_7 $$0SY7Q814VUP$$2NLM Chemicals$$aCalcium
000138485 650_2 $$2MeSH$$aAnimals
000138485 650_2 $$2MeSH$$aCA3 Region, Hippocampal: metabolism
000138485 650_2 $$2MeSH$$aCA3 Region, Hippocampal: pathology
000138485 650_2 $$2MeSH$$aCalcium: metabolism
000138485 650_2 $$2MeSH$$aCulture Media: chemistry
000138485 650_2 $$2MeSH$$aDisease Models, Animal
000138485 650_2 $$2MeSH$$aFrontotemporal Dementia: physiopathology
000138485 650_2 $$2MeSH$$aGlutamic Acid: analysis
000138485 650_2 $$2MeSH$$aHumans
000138485 650_2 $$2MeSH$$aMice
000138485 650_2 $$2MeSH$$aMice, Transgenic
000138485 650_2 $$2MeSH$$aMutation
000138485 650_2 $$2MeSH$$aNeuronal Plasticity
000138485 650_2 $$2MeSH$$aNeurons: chemistry
000138485 650_2 $$2MeSH$$aNeurons: metabolism
000138485 650_2 $$2MeSH$$aNeurons: pathology
000138485 650_2 $$2MeSH$$aOrgan Culture Techniques
000138485 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000138485 650_2 $$2MeSH$$aSynaptic Transmission
000138485 650_2 $$2MeSH$$atau Proteins: chemistry
000138485 650_2 $$2MeSH$$atau Proteins: genetics
000138485 650_2 $$2MeSH$$atau Proteins: metabolism
000138485 7001_ $$0P:(DE-2719)2810335$$aKrüger, Lars$$b1$$udzne
000138485 7001_ $$0P:(DE-2719)2810788$$aSydow, Astrid$$b2$$udzne
000138485 7001_ $$0P:(DE-2719)2811014$$aDennissen, Frank Ja$$b3$$udzne
000138485 7001_ $$0P:(DE-2719)2402361$$aSiskova, Zuzana$$b4$$udzne
000138485 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b5$$udzne
000138485 7001_ $$0P:(DE-2719)2541658$$aMandelkow, Eva-Maria$$b6$$eLast author$$udzne
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