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

Clayton, Emma L. ; Mancuso, Renzo ; Tolstrup Nielsen, Troels LU ; Mizielinska, Sarah ; Holmes, Holly ; Powell, Nicholas ; Norona, Frances ; Overgaard Larsen, Jytte ; Milioto, Carmelo and Wilson, Katherine M. , et al. (2017) In Human Molecular Genetics 26(5). p.873-887
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... (More)

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.

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published
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Human Molecular Genetics
volume
26
issue
5
pages
873 - 887
publisher
Oxford University Press
external identifiers
  • pmid:28093491
  • scopus:85019090616
ISSN
0964-6906
DOI
10.1093/hmg/ddx003
language
English
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yes
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da4c78ea-1d85-4f94-8bbe-298d821e520e
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2019-06-29 22:53:12
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2020-01-16 04:01:02
@article{da4c78ea-1d85-4f94-8bbe-298d821e520e,
  abstract     = {<p>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.</p>},
  author       = {Clayton, Emma L. and Mancuso, Renzo and Tolstrup Nielsen, Troels and Mizielinska, Sarah and Holmes, Holly and Powell, Nicholas and Norona, Frances and Overgaard Larsen, Jytte and Milioto, Carmelo and Wilson, Katherine M. and Lythgoe, Mark F. and Ourselin, Sebastian and Nielsen, Jörgen E. and Johannsen, Peter and Holm, Ida and Collinge, John and Oliver, Peter L. and Gomez-Nicola, Diego and Isaacs, Adrian M.},
  issn         = {0964-6906},
  language     = {eng},
  month        = {03},
  number       = {5},
  pages        = {873--887},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation},
  url          = {http://dx.doi.org/10.1093/hmg/ddx003},
  doi          = {10.1093/hmg/ddx003},
  volume       = {26},
  year         = {2017},
}