We report on a novel transgenic mouse model expressing human full‐length Tau with the Tau mutation A152T (hTauAT), 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, hTauAT causes excitotoxicity mediated by NR2B‐containing NMDA receptors due to enhanced extracellular glutamate.
See also: S Maeda et al
A mouse model of A152T‐variant human Tau, a risk factor for frontotemporal dementia spectrum disorders, suggests that neuronal excitotoxicity, leading to neuronal death, contributes to pathogenesis.
The expression of Tau/A152T leads to Tau pathology in the form of conformational changes, hyperphosphorylation, mis‐sorting, aggregation, neurodegeneration, and neuronal loss in the hippocampus of transgenic mice.
The pathophysiology of Tau/A152T includes enhanced presynaptic neurotransmitter release, leading to increased extracellular glutamate, activation of extrasynaptic (NR2B containing) NMDA receptors, elevated postsynaptic calcium, and enhanced epileptiform activity and results in axonal sprouting in the hippocampal CA3 region.
Pathological effects of Tau/A152T can be ameliorated by stimulating glutamate uptake by astrocytic glutamate transporters.
EMBO Reports (2016) 17: 552–569
- Received September 23, 2015.
- Revision received January 27, 2016.
- Accepted January 28, 2016.
- © 2016 The Authors