Elsevier

Neuroscience

Volume 90, Issue 4, June 1999, Pages 1207-1216
Neuroscience

No hippocampal neuron or synaptic bouton loss in learning-impaired aged β-Amyloid precursor protein-null mice

https://doi.org/10.1016/S0306-4522(98)00645-9Get rights and content

Abstract

Aged β-amyloid precursor protein-null mice were used to investigate the relationship between β-amyloid precursor protein, hippocampal neuron and synaptic bouton number, and cognitive function. Learning and memory performance of aged β-amyloid precursor protein-null mice and age-matched controls were assessed in the Morris water maze. β-Amyloid precursor protein-null mice demonstrated impaired task acquisition as measured by significantly longer swim path lengths, a higher percentage of failed trials, and more frequent thigmotaxis behavior than controls. In a subsequent probe trial, β-amyloid precursor protein-null mice spent significantly less time in the old goal quadrant, and made fewer crossings over the old platform location than did controls. No differences in motor or visual skills were observed which could account for the performance differences. In light of these findings and previous evidence for a role of β-amyloid precursor protein in neuronal maintenance and synaptogenesis, we pursued the hypothesis that the learning impairment of β-amyloid precursor protein-null mice may be a reflection of differences in neuron or synaptophysin-positive presynaptic bouton number. Thus, unbiased stereological analysis was used to estimate neuron and synaptic bouton number in dentate gyrus and hippocampal CA1 of the behaviorally characterized mice. No difference in neuron or synaptophysin-positive presynaptic bouton number was found between the β-amyloid precursor protein-null mice and age-matched controls.

Our results suggest that the learning impairment of β-amyloid precursor protein-null mice is not mediated by a loss of hippocampal neurons or synaptic boutons.

Section snippets

Animals

APP-null mice (B6129-App) (n=12) and control B6129 mice (n=11) were produced from interbreeding of hemizygous (APP+/−mice) [50% B6 and 50% 129/Sv(ev)] and were aged at the Merck Research Laboratories, Rahway, NJ, U.S.A.65 A subpopulation (approximately 15%) of APP-null mice suffer from seizures (primarily caused by disturbance) and/or lethargy (inactivity and non-responsiveness), and were not included in this study since they die within the first 12 months of age. Seizure activity and lethargy

Results

Aged (18–28-months-old) APP-null mice had a 14.7% lower mean body weight than age-matched control mice (controls: 38.7±1.8 g; APP-null: 33.0±2.2 g). This difference however did not reach statistical significance (P=0.06). A similar body weight difference has also been reported between three-month-old APP-null mice and controls.65 Based upon the limited data available there was no indication for a difference in the mean lifespan of APP-null mice when the subgroup which is epileptic and lethargic

Discussion

In the present study we provide further evidence for a role of APP in learning and memory. Aged APP-null mice revealed a learning impairment in the Morris water maze most evident on the first and last day of acquisition. On the second day of acquisition, APP-null mice showed some learning but their performance never reached that of age-matched controls. In the probe trial, APP-null mice did not show a spatial preference for the old goal platform location. This lack of spatial strategy is also

Conclusion

The cognitive deficits observed in Alzheimer's disease (AD) have been linked to several types of neurodegeneration including neuron and synapse loss. Mutations in the APP gene have been identified which alter processing of APP and cause familial AD.17., 49. A loss of the normal function of APP in AD brain cannot be excluded and may contribute to the AD dementia. However, our results suggest that the lack of APP does not lead to significant synaptic bouton and neuron loss, implying that the

Acknowledgements

The authors would like to thank Dr J. Long (GRC, NIA, Baltimore, U.S.A.) for comments on this manuscript, and D. Kurth, R. Lang, C. Bauer, and H. Zysset for technical assistance. We would also like to thank Drs L. Binder (Northwestern University Medical School, Chicago, U.S.A.) and M. Staufenbiel (Novartis Pharma, Basel, Switzerland) for the gift of antibodies. This work was supported by grants from the Swiss National Science Foundation (31-44526.95 and 31-46612.96) and the Swiss Life

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