Dataset Information

Wild-Type, but Not Mutant N296H, Human Tau Restores A?-Mediated Inhibition of LTP in Tau-/- mice.

ABSTRACT: Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that A?-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human MAPT can restore A?-mediated inhibition on a mouse Tau-/- background and whether human tau with an FTD-causing mutation (N296H) can interfere with A?-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full human MAPT locus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on a Tau-/- background. We found that the human wild-type MAPT H1 locus was able to restore A?42-mediated impairment of LTP. In contrast, A?42 did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD). Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that human MAPT is able to restore A?42-mediated inhibition of LTP in Tau-/- mice. These results provide further evidence that tau protein is central to A?-induced LTP impairment and provide a valuable tool for further analysis of the links between A?, human tau and impairment of synaptic function.

SUBMITTER: Vargas-Caballero M

PROVIDER: S-EPMC5401872 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau-/- mice.

Vargas-Caballero Mariana M Denk Franziska F Wobst Heike J HJ Arch Emily E Pegasiou Chrysia-Maria CM Oliver Peter L PL Shipton Olivia A OA Paulsen Ole O Wade-Martins Richard R

Frontiers in neuroscience 20170424

Microtubule associated protein tau (MAPT) is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD). We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP) in mice requires tau. Here, we asked whether expression of human MAPT can restore Aβ-mediated inhibition on a mouse Tau-/- background and whether human tau with an FTD-causing mutation (N296H) can interfere with Aβ-mediated inhibition o ...[more]

PMID: 28484365

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Project description:BackgroundStatus epilepticus (SE) leads to memory impairment following a seizure, attributed to long-term potentiation (LTP) reduction. Thrombin, a coagulation factor that activates protease-activated receptor 1 (PAR1) is involved in cognitive impairment following traumatic brain injury by reducing hippocampal LTP and in seizures as seen in a SE pilocarpine-induced mice model. Thrombin pathway inhibition prevents this cognitive impairment. We evaluated the effect of thrombin pathway inhibition in the pilocarpine-induced SE mice model, on LTP, hippocampal, and serum markers for inflammation, the PAR1 pathway, and neuronal cell damage.MethodsSE was induced by injecting C57BL/6J mice with pilocarpine. Before pilocarpine injection, mice were injected with either the specific thrombin inhibitor α-NAPAP [Nα-(2-naphthalene-sulfonylglycyl)-4-amidino-DL-phenylalaninepiperidide], the PAR1 antagonist SCH79797, or vehicle-only solution. Recordings of excitatory postsynaptic potentials (EPSP) were conducted from hippocampal slices 24 h following pilocarpine injection. Hippocampal real-time PCR for the quantification of the PAR1, prothrombin, and tumor necrosis factor α (TNF-α) mRNA expression levels was conducted. Serum levels of neurofilament light chain (NfL) and TNF-α were measured by a single molecule array assay.ResultsThe EPSP was reduced in the pilocarpine-induced SE mice (p < 0.001). This reduction was prevented by both NAPAP and SCH79797 treatments (p < 0.001 for both treatments). Hippocampal expression of TNF-α was elevated in the pilocarpine-induced SE group compared to the control (p < 0.01), however, serum levels of TNF-α were not changed. NfL levels were elevated in the pilocarpine-induced SE group (p = 0.04) but not in the treated groups.ConclusionsPilocarpine-induced SE reduces LTP, in a thrombin PAR1-related mechanism. Elevation of serum NfL supports neuronal damage accompanying this functional abnormality which may be prevented by PAR1 pathway modulation.

Dataset Information

Wild-Type, but Not Mutant N296H, Human Tau Restores A?-Mediated Inhibition of LTP in Tau-/- mice.

Publications

Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in <i>Tau</i><sup>-/-</sup> mice.

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