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Learning and Memory Deficits in APP Transgenic Mouse Models of Amyloid Deposition

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Abstract

Several different transgenic APP mice develop learning and memory deficits. In some cases the mice have deficits very early in life, while in other instances the mice exhibit deficits only after they have aged and amyloid deposits have accumulated. In many cases, there is a correlation in individual mice of the same age and genotype between the extent of learning and memory deficits and the amounts of deposited amyloid found in the central nervous system. While superficially this might imply that the deposited material is somehow toxic to cognition, it is likely that deposited amyloid is also an index of the overall rate of amyloid production in each mouse. Rate of production would be expected to modify not only the amounts of deposited amyloid, but also other amyloid pools, including soluble, oligomeric, conjugated (e.g. ADDLs) and intracellular. Thus, the deposited material may be an integrated reflection of total Aß production, in addition to indicating the amounts in fibrillar forms. As such, it is conceivable that other Aß pools may be more directly linked to memory deficits. Thus far, the one manipulation found to mitigate the learning and memory deficits in APP transgenic mice is immunotherapy for Aß, either using active or passive immunization against the peptide. These data together with other findings are leading to a conclusion that the fibrillar Aß deposits are not directly linked to the memory deficits in mice, and that some other Aß pool, more readily diminished by immunotherapy, is more directly linked to the mechanisms leading to poor performance in learning and memory tasks.

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REFERENCES

  1. Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., and Gillespie, F. 1995. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527.

    PubMed  Google Scholar 

  2. Greenberg, B. D., Savage, M. J., Howland, D. S., Ali, S. M., Siedlak, S. L., Perry, G., Siman, R., and Scott, R. W. 1996. APP transgenesis: approaches toward the development of animal models for Alzheimer disease neuropathology. Neurobiol. Aging 17:153–171.

    PubMed  Google Scholar 

  3. Justice, A. and Motter, R. 1997. Behavioral characterization of PDAPP transgenic Alzheimer mice. Neurosci. Abstr. 23(2):1637.

    Google Scholar 

  4. Dodart, J. C., Meziane, H., Mathis, C., Bales, K. R., Paul, S. M., and Ungerer, A. 1997. Memory and learning impairment precede amyloid deposition in the V717F PDAPP transgenic mouse. Neurosci. Abstr. 23(2):1637.

    Google Scholar 

  5. Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., and Cole, G. 1996. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102.

    PubMed  Google Scholar 

  6. Routtenberg, A. 1997. Measuring memory in a mouse model of Alzheimer's. Science 277:839–840.

    PubMed  Google Scholar 

  7. Chapman, P. F., White, G. L., Jones, M. W., Cooper-Blacketer, D., Marshall, V. J., Irizarry, M., Younkin, L., Good, M. A., Bliss, T. V., Hyman, B. T., Younkin, S. G., and Hsiao, K. K. 1999. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 2:271–276.

    PubMed  Google Scholar 

  8. Fitzjohn, S. M., Morton, R. A., Kuenzi, F., Rosahl, T. W., Shearman, M., Lewis, H., Smith, D., Reynolds, D. S., Davies, C. H., Collingridge, G. L., and Seabrook, G. R. 2001. Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein. J. Neurosci. 21:4691–4698.

    PubMed  Google Scholar 

  9. Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez-tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M. N., Holcomb, L., Refolo, L., Zenk, B., Hardy, J., and Younkin, S. 1996. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713.

    PubMed  Google Scholar 

  10. Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C. M., Eckman, C., Younkin S., Hsiao, K., and Duff, K. 1998. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4:97–100.

    PubMed  Google Scholar 

  11. Holcomb, L. A., Gordon, M. N., Jantzen, P., Hsiao, K., Duff, K., and Morgan, D. 1999. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: Lack of association with amyloid deposits. Behav. Gen. 29:177–185.

    Google Scholar 

  12. Diamond, D. M., Park, C. R., Heman, K. L., and Rose, G. M. 1999. Exposing rats to a predator impairs spatial working memory in the radial arm water maze. Hippocampus 9:542–551.

    PubMed  Google Scholar 

  13. Gordon, M. N., King, D. L., Diamond, D. M., Jantzen, P. T., Boyett, K. L., Hope, C. E., Hatcher, J. M., DiCarlo, G., Gottschal, P., Morgan, D., and Arendash, G. W. 2001. Correlation between cognitive deficits and Aβ deposits in transgenic APP+PS1 mice. Neurobiol. Aging 22:377–385.

    Google Scholar 

  14. Arendash, G. W., King, D. L., Gordon, M. N., Morgan, D., Hatcher, J. M., Hope, C. E., and Diamond, D. M. 2001. Progressive behavioral impariments in transgenic mice carrying both mutant APP and PS1 transgenes. Brain Res. 891:45–53.

    Google Scholar 

  15. Morgan, D., Diamond, D. M., Gottschall, P. E., Ugen, K. E., Dickey, C., Hardy, J., Duff, K., Jantzen, P., DiCarlo, G., Wilcock, D., Connor, K., Hatcher, J., Hope, C., Gordon, M., and Arendash, G. W. 2000. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408:982–985.

    PubMed  Google Scholar 

  16. Austin, L. A., Arendash, G. W., Gordon, M. N., Diamond, D. M., DiCarlo, G., Dickey, C. A., Ugen, K. E., and Morgan, D. 2003. Short-term A vaccinations do not Improve cognitive performance in cognitively-impaired APP3PS1 mice. Behav. Neurosci. in press.

  17. Gordon, M. N., Holcomb, L. A., Jantzen, P. T., DiCarlo, G., Wilcock, D., Connor, K., Melachrino, J. O., O'Callaghan, J. P., and Morgan, D. 2001. Time course of the development of Alzheimer-like pathology in the doubly transgenic mPS1+mAPP mouse. Exp. Neurol. 173:183–195.

    Google Scholar 

  18. Chen, G., Chen, K. S., Knox, J., Inglis, J., Bernard, A., Martin, S. J., Justice, A., McConlogue, L., Games, D., Freedman, S. B., and Morris, R. G. 2000. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 408:975–979.

    PubMed  Google Scholar 

  19. Dodart, J. C., Mathis, C., Saura, J., Bales, K. R., Paul, S. M., and Ungerer, A. 2000. Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Neurobiol. Dis. 7:71–85.

    PubMed  Google Scholar 

  20. Westerman, M. A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L. H., Carlson, G. A., Younkin, S. G., and Ashe, K. H. 2002. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 22:1858–1867.

    PubMed  Google Scholar 

  21. Dineley, K. T., Westerman, M., Bui, D., Bell, K., Ashe, K. H., and Sweatt, J. D. 2001. Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. J. Neurosci. 21:4125–4133.

    PubMed  Google Scholar 

  22. Puolivali, J., Wang, J., Heikkinen, T., Heikkila, M., Tapiola, T., van Groen, T., and Tanila, H. 2002. Hippocampal A beta 42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice. Neurobiol. Dis. 9:339–347.

    PubMed  Google Scholar 

  23. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Liao, Z., Lieberburg, I., Motter, R., Mutter, L., Soriano, F., Shopp, G., Vasquez, N., Vandevert, C., Walker, S., Wogulis, M., Yednock, T., Games, D., and Seubert, P. 1999. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177.

    PubMed  Google Scholar 

  24. Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., George-Hyslop, P., and Westaway, D. 2000. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408:979–982.

    PubMed  Google Scholar 

  25. Bard, F., Cannon, C., Barbour, R., Burke, R. L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Lieberburg, I., Motter, R., Nguyen, M., Soriano F., Vasquez, N., Weiss, K., Welch, B., Seubert, P., Schenk, D., and Yednock, T. 2000. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6:916–919.

    PubMed  Google Scholar 

  26. Dodart, J. C., Bales, K. R., Gannon, K. S., Greene, S. J., DeMattos, R. B., Mathis, C., DeLong, C. A., Wu, S., Wu, X., Holtzman, D. M., and Paul, S. M. 2002. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat. Neurosci 5:452–457.

    PubMed  Google Scholar 

  27. Kotilinek, L. A., Bacskai, B., Westerman, M., Kawarabayashi, T., Younkin, L., Hyman, B. T., Younkin, S., and Ashe, K. H. 2002. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J. Neurosci. 22:6331–6335.

    Google Scholar 

  28. Morgan, D. and Gordon, M. N. 2002. The amyloid hypothesis of cognitive dysfunction. In: Neuroinflammation Mechanisms and Management, Wood, P. M. (ed.) New York: Humana.

    Google Scholar 

  29. Koistinaho, M., Ort, M., Cimadevilla, J. M., Vondrous, R., Cordell, B., Koistinaho, J., Bures, J., and Higgins, L. S. 2001. Specific spatial learning deficits become severe with age in beta-amyloid precursor protein transgenic mice that harbor diffuse beta-amyloid deposits but do not form plaques. Proc. Natl. Acad. Sci. USA 98:14675–14680.

    PubMed  Google Scholar 

  30. Owen, E. H., Logue, S. F., Rasmussen, D. L., and Wehner, J. M. 1997. Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: Implications of genetic background for single gene mutations and quantitative trait loci analyses. Neurosci 80(4):1087–1099.

    PubMed  Google Scholar 

  31. Gonzalez, R. G., Guimaraes, A. R., Moore, G. J., Crawley, A., Cupples, L. A., and Growdon, J. H. 1996. Quantitative in vivo 31P magnetic resonance spectroscopy of Alzheimer disease. Alzheimer. Dis. Assoc. Disord. 10:46–52.

    PubMed  Google Scholar 

  32. Hardy, J. and Selkoe, D. J. 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297:353–356.

    PubMed  Google Scholar 

  33. Calhoun, M. E., Burgermeister, P., Phinney, A. L., Stalder, M., Tolnay, M., Wiederhold, K. H., Abramowski, D., Sturchler-Pierrat, C., Sommer, B., Staufenbiel, M., and Jucker, M. 1999. Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc. Natl. Acad. Sci. USA 96:14088–14093.

    PubMed  Google Scholar 

  34. Takeuchi, A., Irizarry, M. C., Duff, K., Saido, T. C., Hsiao, A. K., Hasegawa, M., Mann, D. M., Hyman, B. T., and Iwatsubo, T. 2000. Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am. J. Pathol. 157:331–339.

    PubMed  Google Scholar 

  35. Irizarry, M. C., McNamara, M., Fedorchak, K., Hsiao, K., and Hyman, B. T. 1997. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J. Neuropathol. Exp. Neurol. 56:965–973.

    PubMed  Google Scholar 

  36. Irizarry, M. C., Soriano, F., McNamara, M., Page, K. J., Schenk, D., Games, D., and Hyman, B. T. 1997. Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17:7053–7059.

    PubMed  Google Scholar 

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  1. Alzheimer Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, Florida, 33612

    Dave Morgan

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Correspondence to Dave Morgan.

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Morgan, D. Learning and Memory Deficits in APP Transgenic Mouse Models of Amyloid Deposition. Neurochem Res 28, 1029–1034 (2003). https://doi.org/10.1023/A:1023255106106

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