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Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation
Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation
Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.
1-40
Clayton, E.L.
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Mancuso, R.
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Nielsen, T.T.
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Mizielinska, S.
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Holmes, H.
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Powell, N.
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Norona, F.
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Larsen, J.O.
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Milioto, C.
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Wilson, K.M.
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Lythgoe, M.F.
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Ourselin, S.
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Nielsen, J.E.
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Johannsen, P.
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Holm, I.
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Collinge, J.
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Frej, A.
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Oliver, P.L.
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Gomez-Nicola, D.
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Isaacs, A.M.
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Clayton, E.L.
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Mancuso, R.
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Nielsen, T.T.
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Mizielinska, S.
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Holmes, H.
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Powell, N.
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Norona, F.
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Larsen, J.O.
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Milioto, C.
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Wilson, K.M.
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Lythgoe, M.F.
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Ourselin, S.
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Nielsen, J.E.
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Johannsen, P.
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Holm, I.
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Collinge, J.
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Frej, A.
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Oliver, P.L.
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Gomez-Nicola, D.
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Isaacs, A.M.
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Clayton, E.L., Mancuso, R., Nielsen, T.T., Mizielinska, S., Holmes, H., Powell, N., Norona, F., Larsen, J.O., Milioto, C., Wilson, K.M., Lythgoe, M.F., Ourselin, S., Nielsen, J.E., Johannsen, P., Holm, I., Collinge, J., Frej, A., Oliver, P.L., Gomez-Nicola, D. and Isaacs, A.M. (2017) Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation. Human Molecular Genetics, 1-40. (doi:10.1093/hmg/ddx003).

Record type: Article

Abstract

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.

Text Hum. Mol. Genet.-2017-Clayton-hmg_ddx003.pdf - Accepted Manuscript
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Accepted/In Press date: 3 January 2017
e-pub ahead of print date: 16 January 2017
Organisations: Biomedicine

Identifiers

Local EPrints ID: 404775
URI: https://eprints.soton.ac.uk/id/eprint/404775
PURE UUID: 1c0c8262-fc78-46d7-847a-7a485cd32b03
ORCID for D. Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

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Date deposited: 23 Jan 2017 13:57
Last modified: 06 Jun 2018 12:33

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Contributors

Author: E.L. Clayton
Author: R. Mancuso
Author: T.T. Nielsen
Author: S. Mizielinska
Author: H. Holmes
Author: N. Powell
Author: F. Norona
Author: J.O. Larsen
Author: C. Milioto
Author: K.M. Wilson
Author: M.F. Lythgoe
Author: S. Ourselin
Author: J.E. Nielsen
Author: P. Johannsen
Author: I. Holm
Author: J. Collinge
Author: A. Frej
Author: P.L. Oliver
Author: D. Gomez-Nicola ORCID iD
Author: A.M. Isaacs

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