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Wild-type, but not mutant N296H, human tau restores Aβ-mediated inhibition of LTP in Tau-/- mice

Wild-type, but not mutant N296H, human tau restores Aβ-mediated inhibition of LTP in Tau-/- mice
Wild-type, but not mutant N296H, human tau restores Aβ-mediated inhibition of LTP in Tau-/- mice
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 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 Aβ42‐mediated impairment of LTP. In contrast, Aβ42 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 Aβ42‐mediated inhibition of LTP in Tau‐/‐ mice. These results provide further evidence that tau protein is central to Aβ‐induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.
Alzheimer’s disease, Amyloid beta, Frontotemporal Dementia, tau, MAPT, N296H, FTDP-17
1662-4548
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Denk, Franziska
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Wobst, Heike J.
cca1d5ee-300e-448d-835c-d8e15ded60bf
Arch, Emily
13088535-20e6-4f90-81fe-9ad2083f6424
Pegasiou, Chrysia-Maria
70534d16-7533-40c3-b017-2840366f6618
Oliver, Peter
777ec800-10db-4096-947e-8fdbdd85fb88
Shipton, Olivia A.
a28d9db9-e5c3-4fc0-84df-26e45872552e
Paulsen, Ole
fb305f62-2a16-48b0-921a-2cbc59b85c1f
Wade-Martins, Richard
e04b9f70-fc8c-49b0-b994-4dd9f0cc950b
Vargas-Caballero, Mariana
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Denk, Franziska
6bbf478a-9d9a-4b27-a6c2-b529abfe4f5c
Wobst, Heike J.
cca1d5ee-300e-448d-835c-d8e15ded60bf
Arch, Emily
13088535-20e6-4f90-81fe-9ad2083f6424
Pegasiou, Chrysia-Maria
70534d16-7533-40c3-b017-2840366f6618
Oliver, Peter
777ec800-10db-4096-947e-8fdbdd85fb88
Shipton, Olivia A.
a28d9db9-e5c3-4fc0-84df-26e45872552e
Paulsen, Ole
fb305f62-2a16-48b0-921a-2cbc59b85c1f
Wade-Martins, Richard
e04b9f70-fc8c-49b0-b994-4dd9f0cc950b

Vargas-Caballero, Mariana, Denk, Franziska, Wobst, Heike J., Arch, Emily, Pegasiou, Chrysia-Maria, Oliver, Peter, Shipton, Olivia A., Paulsen, Ole and Wade-Martins, Richard (2017) Wild-type, but not mutant N296H, human tau restores Aβ-mediated inhibition of LTP in Tau-/- mice. Frontiers in Neuroscience. (doi:10.3389/fnins.2017.00201).

Record type: Article

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 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 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 Aβ42‐mediated impairment of LTP. In contrast, Aβ42 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 Aβ42‐mediated inhibition of LTP in Tau‐/‐ mice. These results provide further evidence that tau protein is central to Aβ‐induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.

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Accepted/In Press date: 24 March 2017
e-pub ahead of print date: 24 April 2017
Published date: 24 April 2017
Keywords: Alzheimer’s disease, Amyloid beta, Frontotemporal Dementia, tau, MAPT, N296H, FTDP-17
Organisations: Biomedicine, Centre for Biological Sciences

Identifiers

Local EPrints ID: 408454
URI: http://eprints.soton.ac.uk/id/eprint/408454
ISSN: 1662-4548
PURE UUID: aa786231-f041-4808-8b88-7125d26cd6d6
ORCID for Mariana Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001

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Date deposited: 20 May 2017 04:05
Last modified: 06 Jun 2024 01:50

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Contributors

Author: Franziska Denk
Author: Heike J. Wobst
Author: Emily Arch
Author: Chrysia-Maria Pegasiou
Author: Peter Oliver
Author: Olivia A. Shipton
Author: Ole Paulsen
Author: Richard Wade-Martins

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