Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent

D Ryan, D Koss, E Porcu, H Woodcock, L Robinson, B Platt, G Riedel

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

We recently generated an advanced mouse model of Alzheimer's disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein (APP) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1Triple mice aged 4-12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic APP mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PSAPP mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models.
Original languageEnglish
Pages (from-to)2603-2619
Number of pages17
JournalCellular and Molecular Life Sciences
Volume70
Issue number14
Early online date28 Mar 2013
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Water
Alzheimer Disease
Amyloid beta-Protein Precursor
Spatial Learning
Presenilins
Short-Term Memory
Dementia
Observation
Phenotype
Genes
Spatial Memory
Recognition (Psychology)

Keywords

  • aging
  • Alzheimer disease
  • amyloid beta-protein precursor
  • animals
  • behavior, animal
  • brain
  • calcium-calmodulin-dependent protein kinase type 2
  • disease models, animal
  • female
  • gene knock-in techniques
  • humans
  • male
  • maze learning
  • memory
  • mice
  • mice, transgenic
  • presenilins
  • promoter regions, genetic
  • tau proteins
  • knock-in mouse
  • amyloid
  • tau
  • spatial cognition
  • learning

Cite this

Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent. / Ryan, D; Koss, D; Porcu, E; Woodcock, H; Robinson, L; Platt, B; Riedel, G.

In: Cellular and Molecular Life Sciences, Vol. 70, No. 14, 07.2013, p. 2603-2619.

Research output: Contribution to journalArticle

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AB - We recently generated an advanced mouse model of Alzheimer's disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein (APP) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1Triple mice aged 4-12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic APP mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PSAPP mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models.

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KW - presenilins

KW - promoter regions, genetic

KW - tau proteins

KW - knock-in mouse

KW - amyloid

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JO - Cellular and Molecular Life Sciences

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