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.

Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes

Abstract

Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (P52) genes1. The mutant APPK670N,M67M transgenic line, Tg2576, shows markedly elevated amyloid β-protein (AP) levels at an early age and, by 9–12 months, develops extracellular AD-type Ap deposits in the cortex and hippocampus2. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide Aβ342(43) (ref. 3). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M46L transgenic line develop large numbers of fibrillar Aβ deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 litter-mates. In the period preceding overt Aβ deposition, the doubly transgenic mice show a selective 41% increase in Aβ42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a P51 mutation, which causes a modest increase in Aβ42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a “Y” maze before substantial Aβ deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Duff, K., et al. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713 (1996).

    Article  CAS  Google Scholar 

  4. Gravina, S., et al. Amyloid beta protein (Aβ) in Alzheimer's disease brain: Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Aβ40 or Aβ42(43). J. Biol. Chem. 270, 7013–7016 (1995).

    Article  CAS  Google Scholar 

  5. Scheuner, D., et al. Secreted amyloid β-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 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Citron, M., et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72 (1997).

    Article  CAS  Google Scholar 

  8. Good, M. & Honey, R. Dissociable effects of selective lesions to hippocampal subsystems on exploratory behavior, contextual learning and spatial learning. Behav. Neurosci. 111, 487–493 (1997).

    Article  CAS  Google Scholar 

  9. Logue, S., Paylor, R. & Wehner, J. Hippocampal lesions cause learning deficiencies in the Morris water maze and conditioned fear task. Behav. Neurosci. 111,104–113 (1997).

    Article  CAS  Google Scholar 

  10. Laghmouch, A., Bertholet, J. & Crusio, W. Hippocampal morphology and open field behavior in Mus musculus domesticus and Mus spretus inbred mice. Behav. Genet. 27, 67–73 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Hsiao, K., et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 5, 1203–1218 (1995).

    Article  Google Scholar 

  13. Wild-Bode, C., et al. Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J. Biol. Chem. 272,16085–16088 (1997).

    Article  CAS  Google Scholar 

  14. Hartmann, T., et al. Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides. Nature Med. 3, 1016–1020 (1997).

    Article  CAS  Google Scholar 

  15. LaFerla, F.M., Troncoso, J.C., Strickland, D.K., Kawas, C.H. & Jay, G. Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Aβ stabilization. J. Clin. Invest. 100, 310–320 (1997).

    Article  CAS  Google Scholar 

  16. Masliah, E., et al. Comparison of neurodegenerative pathology in transgenic mice overexpressing the V717F β-amyloid precursor protein and Alzheimer's disease. J. Neurosci. 16, 5795–5811.

    Article  CAS  Google Scholar 

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

  18. Maurice, T., et al. Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res. 706, 181 (1996).

    Article  CAS  Google Scholar 

  19. Gordon, M., et al. Exaggerated astrocyte reactivity after nigrostriatal deafferenta-tion in the aged rat. J. Comp. Neurol. 388, 106–119 (1997).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karen Duff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holcomb, L., Gordon, M., McGowan, E. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4, 97–100 (1998). https://doi.org/10.1038/nm0198-097

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0198-097

This article is cited by

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