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

Research output: Contribution to journalArticle


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.


  • Emma L. Clayton
  • Renzo Mancuso
  • Troels Tolstrup Nielsen
  • Sarah Mizielinska
  • Holly Holmes
  • Nicholas Powell
  • Frances Norona
  • Jytte Overgaard Larsen
  • Carmelo Milioto
  • Katherine M. Wilson
  • Mark F. Lythgoe
  • Sebastian Ourselin
  • Jörgen E. Nielsen
  • Peter Johannsen
  • Ida Holm
  • John Collinge
  • Peter L. Oliver
  • Diego Gomez-Nicola
  • Adrian M. Isaacs
  • Elisabet Englund (Contributor)
  • FReJA
External organisations
  • University College London
  • University of Southampton
  • University of Copenhagen
  • Panum Institute
  • Randers Regional Hospital
  • Aarhus University
  • University of Oxford
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
Original languageEnglish
Pages (from-to)873-887
JournalHuman Molecular Genetics
Issue number5
Publication statusPublished - 2017 Mar 1
Publication categoryResearch