Age-dependent cognitive decline in the APP23 model precedes amyloid deposition

Authors

  • Debby Van Dam,

    1. Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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  • Rudi D'Hooge,

    1. Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
    2. Department of Neurology/Memory clinic, Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium
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  • Matthias Staufenbiel,

    1. Novartis Pharma, Inc., S-386.806, CH-4002 Basel, Switzerland
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  • Chris Van Ginneken,

    1. Laboratory of Veterinary Anatomy and Embryology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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  • Frans Van Meir,

    1. Laboratory of Cell Biology and Histology, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerpen, Belgium
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  • Peter P. De Deyn

    1. Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
    2. Department of Neurology/Memory clinic, Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium
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: Professor R. D'Hooge, as above.
E-mail: rudi.dhooge@ua.ac.be

Abstract

Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6–8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-β1–42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-β1–42 peptides, but probe trial performance did correlate negatively with soluble amyloid-β brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model.

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