Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse

Kaja Plucińska, Barry Crouch, Jie M. Yeap, Sandra Stoppelkamp, Gernot Riedel, Bettina Platt

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Gene mutations within Amyloid Precursor Protein (APP or AβPP) and/or Presenilin 1 (PS1) are determinant of familial Alzheimer’s disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APPSwe/Lon and investigated histopathology and behavioural changes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1A246E) line to assess the impact of this risk gene combination in mice. Immunohistochemistry determined Aβ-pathology, astrogliosis (via GFAP labelling) and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels of intracellular Aβ in CA1, dentate gyrus and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical build-up of soluble and fibrillar Aβ. Amyloid plaques were sparse in aged PLB2APP
mice, co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1
mice. Behaviourally, habituation to a novel environment, circadian activity and spatial reference memory were assessed at 6 and 12 months. Habituation was delayed in 6-month old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12months, particularly during the dark phase. Spatial learning in the water maze task was impaired in PLB2APP mice independent of PS1expression; this was associated with a reduced employment of spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without over-expression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1, including a shift from hippocampal to cortical Aβ pathology, alongside
reduced deficits in spatial learning.
Original languageEnglish
Pages (from-to)165-180
Number of pages15
JournalJournal of Alzheimer's Disease
Issue number1
Early online date18 Jul 2018
Publication statusPublished - 7 Aug 2018

Bibliographical note

Funding sources
KP was funded by a donation from Roemex Ltd (Mr. R. Simcox) to BP and GR. The
project was in part supported by the Alzheimer’s Research UK (ARUK) Scotland
network and by an Alzheimer’s Society project grant (AS-PG-14-039) to BP and GR.


  • amyloid
  • inflammation
  • habituation
  • cognition
  • spatial learning
  • search strategies


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