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

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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, Jorgen E. Nielsen, Peter Johannsen, Ida Holm, John Collinge, Peter L. Oliver, Diego Gomez-Nicola, Adrian M. Isaacs

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.
Original languageEnglish
JournalHuman Molecular Genetics
Volume26
Issue number5
Pages (from-to)873-887
Number of pages15
ISSN0964-6906
DOIs
Publication statusPublished - 2017

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