Skip to main content
Log in

Behavioral Changes in Transgenic Mice Expressing Both Amyloid Precursor Protein and Presenilin-1 Mutations: Lack of Association with Amyloid Deposits

  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

Mutations in the amyloid precursor protein (mAPP) and in presenilin 1 (mPS1) have both been linked to increased production of the β-amyloid peptide (Aβ). Doubly transgenic mice produced by mating of a parental line carrying the “Swedish” (K670N/M671L) APP mutation with a FAD4 (M146L) mutant presenilin 1 line developed numerous fibrillar Aβ deposits by 6 months of age. Prior work demonstrated that mAPP and doubly transgenic (mAPP/mPS1) mice have deficits in Y-maze alternation behavior as early as 3 months of age. Increased activity was also apparent in the mAPP/mPS1 mice at this time point. These changes in Y-maze performance persisted in mAPP/mPS1 mice at 6 and 9 months of age. The mPS1 singly transgenic mice were not impaired on this task at any age. Six- and nine-month-old mice were also tested for spatial navigation behavior in the Morris water maze. In training trials, no differences in escape latency were detected among the four genotypes. In probe trials, no differences were detected in either the time spent in the trained quadrant or the number of platform crossings among the four groups. Histological staining for Aβ amyloid deposits indicates that all doubly transgenic mice have amyloid deposits by 6 months of age (roughly 25 mice examined thus far), yet no 3-month-old mice have been found with deposits. Aβ immunostaining confirmed that the 9-month-old mice tested behaviorally also have Aβ deposits. Thus, doubly transgenic mice exhibited changes in Y-maze performance prior to the formation of amyloid deposits, which are essentially unchanged as the deposits increase in number and size to 9 months of age. Yet these mice fail to reveal impairments in spatial navigation at 6 or 9 months in spite of the increasing plaque burden. These data indicate that Aβ deposits alone are not sufficient to cause robust spatial memory impairment in mice of this mixed background lineage and age.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Cai, X.-D., Golde, T. E., and Younkin, S. G. (1993). Release of excess amyloid B-protein from a mutant amyloid B protein precursor. Science 259:514-516.

    PubMed  Google Scholar 

  • Campion, D., Brice, A., Dumanchin, C., Puel, M., Baulac, M., De La Sayette, V., Hannequin, D., Duyckaerts, C., Michon, A., Martin, C., Moreau, V., Penet, C., Martinez, M. Clerget-Darpoux, F., Agid, Y., and Frebourg, T. (1996). A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. NeuroReport 7:1582-1584.

    PubMed  Google Scholar 

  • Carlson, G. A., Borchelt, D. R., Dake, A., Turner, S., Danielson, V., Coffin, J. D., Eckman, C., Meiners, J., Nilsen, S., Younkin, S. G., and Hsiao, K. (1997). Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum. Mol. Genet. 6(11):1951-1959.

    PubMed  Google Scholar 

  • Citron, M., Oltersdorf, T., Haass, C., McConolgue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., and Selkoe, D. J. (1992). Mutation of the B-amyloid precursor protein in familial Alzheimer's disease increases B-protein production. Nature 360:672-674.

    PubMed  Google Scholar 

  • D'Hooge, R., Nagels, G., Westland, C. E., Mucke, L., and DeDeyn, P. P. (1996). Spatial learning deficit in mice expressing human 751-amino acid beta-amyloid precursor protein. NeuroReport 7:2807-2811.

    PubMed  Google Scholar 

  • 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. Soc. Neurosci. Abstr. 23:1637.

    Google Scholar 

  • Douglas, R. J. (1990). Spontaneous alternation behavior and the brain. In Denber, W. N., and Richman, L. L.(eds.), Spontaneous Alternation Behavior, Springer-Verlag, New York, pp. 73-109.

    Google Scholar 

  • 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-B42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710-713.

    PubMed  Google Scholar 

  • Durkin, T. P. (1994). Spatial working memory over long retention intervals: dependence on sustained cholinergic activation in the septohippocampal or nucleus basalis magnocellularis-cortical pathways? Neuroscience 62:681-693.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Gordon, M. N., Schreier, W. A., Ou, X., Holcomb, L. A., and Morgan, D. G. (1997). Exaggerated astrocyte reactivity after nigrostriatal deafferentation in the aged rat. J. Comp. Neurol. 388:106-119.

    PubMed  Google Scholar 

  • Gordon, M. N., Gottschall, P. E., O'Callaghan, J. P., Hsiao, K., Duff, K., and Morgan, D. G. (1998). Progression of neuropathology in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations. Soc. Neurosci. Abstr. 24:1502.

    Google Scholar 

  • Haltia, M., Viitanen, M., Sulkava, R., Ala-Hurula, V., Poyhonen, M., Goldfarb, L., Brown, P., Levy, E., Houlden, H., Crook, R., Goate, A., Clark, R., Korenblat, K., Pandit, S., Keller, H. D., Lilius, L., Liu, L., Axelman, K., Forsell, L., Winblad, B., Lannfelt, L., and Hardy, J. (1994). Chromosome 14-encoded Alzheimer's disease: Genetic and clinicopathological description. Ann. Neurol. 36:362-367.

    PubMed  Google Scholar 

  • Hardy, J. (1997). Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci, 20:154-160.

    PubMed  Google Scholar 

  • 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. Nature Med. 4:97-100.

    PubMed  Google Scholar 

  • Hsiao, K., Borchelt, D. R., Olson, K., Johannsdottir, R., Kitt, C., Yunis, W., Xu, S., Eckman, C., Younkin, S., Price, D., Iadecola, C., Clark, H. B., and Carlson, G. (1995). Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 15:1203-1218.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    Google Scholar 

  • Kennedy, A. M., Newman, S. K., Frackowiak, R. S. J., Cunningham, V. J., Rogues, P., Stevens, J., Neary, D., Bruton, C. J., Warrington, E. K., and Rossor, M. N. (1995). Chromosome 14 linked familial Alzheimer's disease A clinico-pathological study of a single pedigree. Brain 118:185-205.

    PubMed  Google Scholar 

  • La Ferla, F. M., Tinkle, B. T., Bierich, C. J., Haudenschild, C., and Jay, G. (1995). The Alzheimer's AB peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genet. 9:21-30.

    PubMed  Google Scholar 

  • Lalonde, R., and Thifault, S. (1994). Absence of an association between motor coordination and spatial orientation in lurcher mutant mice. Behav. Genet. 24:497-501.

    PubMed  Google Scholar 

  • Londei, T., Misto, R., Vismara, C., and Leone, V. G. (1995). Congenital brain damage spares the basic patterns of parental behavior in affected mice. Brain Res. 677:61-68.

    PubMed  Google Scholar 

  • MacDonald, M. P., and Overmier, J. B. (1998). Present imperfect. A critical review of animal models of mnemonic impairments in Alzheimer's disease. Neurosci. Biobehav. Rev. 22:99-120.

    PubMed  Google Scholar 

  • Maurice, T., Lockhart, B. P., and Privat, A. (1996). Amnesia induced in mice by centrally administered B-amyloid peptides involves cholinergic dysfunction. Brain Res. 706:181-193.

    PubMed  Google Scholar 

  • Moechars, D., Lorent, K., De Strooper, B., Dewachter, I., and Van Leuven, F. (1996). Expression in brain of amyloid precursor protein mutated in the A-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice. EMBO J. 15:1265-1274.

    PubMed  Google Scholar 

  • Moran, P. M., Higgins, L. S., Cordell, B., and Moser, P. C. (1995). Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human B-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 92:5341-5345.

    PubMed  Google Scholar 

  • Morgan, D., Holcomb, L., Saad, I., Gordon, M., and Maines, M. (1998). Impaired spatial navigation learning in transgenic mice over-expressing heme oxygenase-1.Brain Res. 808:110-112.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., Larson, E., Levy-Lahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., Selkoe, D., and Younkin, S. (1996). Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2:864-870.

    PubMed  Google Scholar 

  • Steel, K. P., and Hardisty, R. (1996). Assessing hearing, vision and balance in mice. In What's wrong with my mouse? New interplays between mouse genetics and behavior, Society for Neuroscience Short Course Syllabus.

  • Still, A. W. (1966). Memory and spontaneous alternation in the rat. Nature 210:400-401.

    PubMed  Google Scholar 

  • Wolfer, D. P., Muller, U., Stagliar, M., and Lipp, H. P. (1997). Assessing the effects of the 129/Sv genetic background on swimming navigation learning in transgenic mutants: A study using mice with a modified beta-amyloid precursor protein gene. Brain Res. 771:1-13.

    PubMed  Google Scholar 

  • Zheng, H., Jiang, M., Trumbauer, M. E., Sirinathsinghji, D. J. S., Hopkins, R., Smith, D. W., Heavens, R. P., Dawson, G. R., Boyce, S., Conner, M. W., Stevens, K. A., Slunt, H. H., Sisodia, S. S., Chen, H. Y., and Van der Ploeg, L. H. T. (1995). ß-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525-531.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holcomb, L.A., Gordon, M.N., Jantzen, P. et al. Behavioral Changes in Transgenic Mice Expressing Both Amyloid Precursor Protein and Presenilin-1 Mutations: Lack of Association with Amyloid Deposits. Behav Genet 29, 177–185 (1999). https://doi.org/10.1023/A:1021691918517

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1021691918517

Navigation