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

Research output: Contribution to journalArticle

5 Downloads (Pure)

Abstract

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
Volume65
Issue number1
Early online date18 Jul 2018
DOIs
Publication statusPublished - 7 Aug 2018

Fingerprint

Presenilin-1
Phenotype
Presenilins
Pathology
Amyloid beta-Protein Precursor
Dentate Gyrus
Amyloid Plaques
Genes
Alzheimer Disease
Theoretical Models
Immunohistochemistry
Mutation
Water
Brain
Spatial Learning

Keywords

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

Cite this

Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse. / Plucińska, Kaja; Crouch, Barry; Yeap, Jie M.; Stoppelkamp, Sandra; Riedel, Gernot; Platt, Bettina.

In: Journal of Alzheimer's Disease, Vol. 65, No. 1, 07.08.2018, p. 165-180.

Research output: Contribution to journalArticle

@article{4702ef2bdeb54c0aa1b6af303290b596,
title = "Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse",
abstract = "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 PLB2APPmice, co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1mice. 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.",
keywords = "amyloid, inflammation, habituation, cognition, spatial learning, search strategies",
author = "Kaja Plucińska and Barry Crouch and Yeap, {Jie M.} and Sandra Stoppelkamp and Gernot Riedel and Bettina Platt",
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.",
year = "2018",
month = "8",
day = "7",
doi = "10.3233/JAD-180336",
language = "English",
volume = "65",
pages = "165--180",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "1",

}

TY - JOUR

T1 - Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse

AU - Plucińska, Kaja

AU - Crouch, Barry

AU - Yeap, Jie M.

AU - Stoppelkamp, Sandra

AU - Riedel, Gernot

AU - Platt, Bettina

N1 - 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.

PY - 2018/8/7

Y1 - 2018/8/7

N2 - 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 PLB2APPmice, co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1mice. 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.

AB - 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 PLB2APPmice, co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1mice. 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.

KW - amyloid

KW - inflammation

KW - habituation

KW - cognition

KW - spatial learning

KW - search strategies

U2 - 10.3233/JAD-180336

DO - 10.3233/JAD-180336

M3 - Article

VL - 65

SP - 165

EP - 180

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 1

ER -