Spatial learning impairments in PLB1 Triple knock-in Alzheimer mice are task-specific and age-dependent
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
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
Received: 15 September 2012 / Revised: 27 February 2013 / Accepted: 28 February 2013 / Published online: 28 March 2013 © Springer Basel 2013
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 ADrelevant 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
D. Ryan · D. Koss · E. Porcu · H. Woodcock · L. Robinson · B. Platt · G. Riedel (*) School of Medical Sciences, College of Life Sciences and Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK e-mail: [email protected] B. Platt e-mail: [email protected]
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. Keywords Knock-in mouse · Amyloid · Tau · Spatial cognition · Learning · Memory
Introduction Alzheimer’s disease (AD) is the most common agerelated neurodegenerative disease and the primary cause of dementia. With the number of sufferers and the associated healthcare burden continuously rising, effective treatment strategies are urgently required. The identification of specific mutations in familial forms of AD has led to a greater understanding of the disease process, and owing to the development of transgene technology, numerous experimental models expressing human mutant amyloid-precursor protein (APP), presenilin 1 or 2 (PS-1 or 2), and tau protein have m
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