Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice

Nature Neuroscience volume 2, pages 271–276 (1999)Cite this article

Abstract

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Aged APP695SWE mice demonstrate abnormal long-term synaptic plasticity despite otherwise normal synaptic physiology.
Figure 2: LTP is impaired in the dentate gyrus in aged APP695SWE transgenic mice in vivo.
Figure 3: Behavioral deficits in aged APP695SWE transgenic mice are correlated with deficits in hippocampal synaptic plasticity.
Figure 4: Aβ immunostaining with red cy3-labelled biotinylated 3D6 (ref. 19) in a 250 μm-thick section used for electrophysiology studies.

Similar content being viewed by others

References

  1. Citron, M. et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360 , 672–674 (1992).

    Article  CAS  Google Scholar 

  2. Cai, X., Golde, T. E. & Younkin, S. G. Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science 259, 514–516 (1993).

    Article  CAS  Google Scholar 

  3. Suzuki, N. et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1335–1340 ( 1994).

    Google Scholar 

  4. Borchelt, D. R. et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1–42/1–40 ration in vitro and in vivo . Neuron 17, 1005–1013 (1996).

    Article  CAS  Google Scholar 

  5. Duff, K. et al. Increased amyloid-beta 42(43) in brains of mice expressing presenilin 1. Nature 383, 710–713 (1996).

    Article  CAS  Google Scholar 

  6. Goate, A. M. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    Article  CAS  Google Scholar 

  7. Mullan, M. et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid. Nat. Genet. 1, 345–347 ( 1992).

    Article  CAS  Google Scholar 

  8. Chartier-Harlin, M. C. et al. Early-onset Alzheimer's disease caused by mutation at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846 (1991).

    Article  CAS  Google Scholar 

  9. Murrell, J., Farlow, M., Getti, B. & Benson, M. D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254, 97–99 (1991).

    Article  CAS  Google Scholar 

  10. Hendriks, L. et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nat. Genet. 1, 218–221 ( 1992).

    Article  CAS  Google Scholar 

  11. Eckman, C. B. et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A-beta 42(43). Hum. Mol. Genet. 6, 2087–2089 (1997).

    Article  CAS  Google Scholar 

  12. Hardy, J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20, 154–159 ( 1997).

    Article  CAS  Google Scholar 

  13. Hsiao, K. K. et al. Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  14. Irizarry, M. C., McNamara, M., Fedorchak, K., Hsiao, K. K. & Hyman, B. T. APPSW transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J. Neuropathol. Exp. Neurol. 56, 965–973 (1997).

    Article  CAS  Google Scholar 

  15. Frautschy, S. A. et al. Microglial response to amyloid plaques in APPSW transgenic mice. Am. J. Pathol. 152, 307 –317 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory—long-term potentiation in the hippocampus. Nature 361, 31–39 ( 1993).

    Article  CAS  Google Scholar 

  17. Errington, M. L., Bliss, T. V. P., Morris, R. J., Laroche, S. & Davis, S. Long-term potentiation in awake mutant mice. Nature 387, 666–667 (1997).

    Article  CAS  Google Scholar 

  18. Zucker, R. S. Short-term synaptic plasticity. Annu. Rev. Neurosci. 12, 13–31 (1989).

    Article  CAS  Google Scholar 

  19. Hyman, B. T., Van Hoesen, G. W., Kromer, L. J. & Damasio, A. R. Perforant pathway change and the memory impairment of Alzheimer's disease. Ann. Neurol. 20, 473–482 (1986).

    Article  Google Scholar 

  20. Finch, C. E. Neuron atrophy during aging: programmed or sporadic? Trends Neurosci. 16, 104–110 ( 1993).

    Article  CAS  Google Scholar 

  21. Schauwecker, P. E. & Steward, O. Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc. Natl. Acad. Sci. USA 94, 4103–4108 (1997).

    Article  CAS  Google Scholar 

  22. Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448– 6453 (1998).

    Article  CAS  Google Scholar 

  23. Nalbantoglu, J. et al. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387, 500–505 (1997).

    Article  CAS  Google Scholar 

  24. Südhof, T. C. The synaptic vesicle cycle: a cascade of protein–protein interaction. Nature 375, 645–653 (1995).

    Article  Google Scholar 

  25. Luthi, A., Laurent, J. P., Figurov, A., Muller, D. & Schachner, M. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779 (1994).

    Article  Google Scholar 

  26. Dragunow, M. A role for immediate-early transcription factors in learning and memory. Behav. Genet. 26, 293–299 (1996).

    Article  CAS  Google Scholar 

  27. Ikezu, T. et al. Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP. EMBO J. 15, 2468–2475 (1996).

    Article  CAS  Google Scholar 

  28. Castillo, P. E. et al. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature 388, 590– 593 (1997).

    Article  CAS  Google Scholar 

  29. Kang, H., Welcher, A. A., Shelton, D. & Schuman, E. M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653– 664 (1997).

    Article  CAS  Google Scholar 

  30. Giese, K. P., Federov, N. B., Filipkowski, R. K. & Silva, A. J. Autophosphorylation at threonine 286 of the α calcium-calmodulin-kinase II in LTP and learning. Science 279, 870 (1998).

    Article  CAS  Google Scholar 

  31. Klann, E., Chen, S. J. & Sweatt, J. D. Persistent protein kinase activation in the maintenance phase of long-term potentiation. J. Biol. Chem. 266 , 24253–24256 (1991).

    CAS  PubMed  Google Scholar 

  32. Winder, D. G., Mansuy, I. M., Osman, M., Moallem, T. M. & Kandel, E. R. Genetic and pharmacological evidence for a novel, intermediate phase of long-term potentiation suppressed by calcineurin. Cell 92, 25–37 ( 1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the NIH (NS33249 (KH), K08-AG00793 (MI and BH), and AG08487 (BH)), the Mayo Medical Foundation (KH, SY) and the Medical Research Council (PC).

Author information

Authors and Affiliations

  1. Cardiff School of Biosciences, Cardiff University, Cardiff, CF1 3US, Wales, UK

    Paul F. Chapman, Gail L. White & Vanessa J. Marshall

  2. Division of Neurophysiology, National Institute of Medical Research, Mill Hill, London, NW7 1AA, UK

    Matthew W. Jones & T. V. P. Bliss

  3. Department of Neurology, University of Minnesota Medical School, Minneapolis, 55455, Minnesota, USA

    Deirdre Cooper-Blacketer & Karen K. Hsiao

  4. Department of Neurology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Michael Irizarry & Bradley T. Hyman

  5. Mayo Clinic Jacksonville, Jacksonville, 32224, Florida, USA

    Linda Younkin & Steven G. Younkin

  6. School of Psychology, Cardiff University, Cardiff, CF1 3US, Wales, UK

    Mark A. Good

Authors
  1. Paul F. Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gail L. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew W. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deirdre Cooper-Blacketer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vanessa J. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Irizarry
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Linda Younkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark A. Good
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T. V. P. Bliss
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bradley T. Hyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Steven G. Younkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Karen K. Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen K. Hsiao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chapman, P., White, G., Jones, M. et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2, 271–276 (1999). https://doi.org/10.1038/6374

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/6374

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing