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A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease

Abstract

Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive β-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze1, hAPP mice are impaired before and after amyloid plaque deposition2,3,4,5,6,7. Here we show, using a new water-maze training protocol, that PDAPP mice8 also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with β-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that Aβ overexpression and/or Aβ plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.

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Figure 1: Age-related and age-independent deficits in spatial learning in PDAPP mice.
Figure 2: Swim speeds and swim paths.
Figure 3: An age-related decline in learning capacity in PDAPP mice.The y axes show the number of successive spatial locations of a single hidden platform learned to criterion in 10 d of training (‘learning capacity’).
Figure 4: The relationship between performance and β-amyloid plaque deposition.
Figure 5: Normal object-recognition memory.

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Acknowledgements

This work was supported by grants from the MRC and the Cunningham Trust. We are indebted to Bill Nailon (CJD Surveillance Unit, Edinburgh) and Karen Khan (Elan Pharmaceuticals) for assistance with immunocytochemistry and image analysis.

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Correspondence to Richard G. M. Morris.

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Chen, G., Chen, K., Knox, J. et al. A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408, 975–979 (2000). https://doi.org/10.1038/35050103

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