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.

Mancuso, RenzoUniversity of Southampton (author)
Tolstrup Nielsen, TroelsUniversity of Copenhagen(Swepub:lu)mphy-tto (author)
Mizielinska, SarahUniversity College London (author)
Holmes, HollyUniversity College London (author)
Powell, NicholasPanum Institute,University College London (author)
Norona, FrancesUniversity College London (author)
Overgaard Larsen, JytteUniversity College London (author)
Milioto, CarmeloUniversity College London (author)
Wilson, Katherine M.University College London (author)
Lythgoe, Mark F.University College London (author)
Ourselin, SebastianPanum Institute (author)
Nielsen, Jörgen E.University of Copenhagen (author)
Johannsen, PeterUniversity of Copenhagen (author)
Holm, IdaAarhus University,Randers Regional Hospital (author)
Collinge, JohnUniversity College London (author)
Oliver, Peter L.University of Oxford (author)
Gomez-Nicola, DiegoUniversity of Southampton (author)
Isaacs, Adrian M.University College London (author)
Englund, ElisabetLund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)pat-een (creator_code:cre_t)
University College LondonUniversity of Southampton (creator_code:org_t)
FReJA

In:Human Molecular Genetics: Oxford University Press (OUP)26:5, s. 873-8870964-69061460-2083

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Neurology

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