title: Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation.
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.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Clayton
authors.affiliation: Biological Sciences, University of Southampton, Southampton General Hospital, South Laboratory and Pathology Block, Tremona Road, Southampton SO166YD, UK.
authors.forename: Renzo
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Troels Tolstrup
authors.initials: TT
authors.lastname: Nielsen
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mizielinska
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Holmes
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, 72 Huntley Street, London WC1E 6DD, UK.|Faculty of Health and Medical Sciences, Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Powell
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Norona
authors.affiliation: Translational Imaging Group, Centre for Medical Image Computing (CMIC), University College London, UK.
authors.forename: Jytte Overgaard
authors.initials: JO
authors.lastname: Larsen
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Milioto
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Wilson
authors.affiliation: Centre for Advanced Biomedical Imaging, Division of Medicine and Institute of Child Health, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.affiliation: Faculty of Health and Medical Sciences, Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ourselin
authors.affiliation: Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Denmark.|Section of Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jörgen E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Johannsen
authors.affiliation: Laboratory for Experimental Neuropathology, Department of Pathology, Randers Hospital, DK-8930 Randers NØ, Denmark.|Institute of Clinical Medicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Holm
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.|MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: Biological Sciences, University of Southampton, Southampton General Hospital, South Laboratory and Pathology Block, Tremona Road, Southampton SO166YD, UK.
authors.forename: Diego
authors.initials: D
authors.lastname: Gomez-Nicola
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
mesh_terms: D000818:Animals; D003704:Dementia / Q000235:genetics; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D014060:Tongue Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins