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.

The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation

Abstract

Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid β-protein (Aβ) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Aβ sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Aβ42 and Aβ40 levels in plasma. Additionally, low levels of Aβ42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Aβ with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Aβ. The finding of increased protofibril formation and decreased Aβ plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Aβ protofibril formation leading to accelerated buildup of insoluble Aβ intra- and/or extracellularly.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The intra-Aβ mutations.
Figure 2: Plasma Aβ levels in the family carrying the Arctic mutation.
Figure 3: Radiosequencing of Aβ 3H-phenylalanine-labeled Aβ and p3.
Figure 4: Size exclusion chromatograms of Aβ.
Figure 5: Kinetics of Aβ. Kinetics of Aβ1-40wt (88 μM) (a) and Aβ1-40Arc (92 μM) (b) monitoring decline in monomeric/dimeric peak area () and concomitant increase and subsequent decline of protofibrillar peak area ().
Figure 6: Electron micrographs of Aβ protofibrils.

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    Selkoe, D. J. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399, A23–A31 (1999).

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Citron, M. et al. Excessive production of amyloid β-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer's disease mutation. Proc. Natl. Acad. Sci. USA 91, 11993–11997 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Johnston, J. A. et al. Increased β-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the Swedish Alzheimer's disease APP670/671 mutation. FEBS Lett. 354, 274–278 (1994).

    CAS  Article  Google Scholar 

  6. 6

    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. Nat. Med. 2, 864–869 (1996).

    CAS  Article  Google Scholar 

  7. 7

    Levy, E. et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    De Jonghe, C. et al. Flemish and Dutch mutations in amyloid β precursor protein have different effects on amyloid β secretion. Neurobiol. Dis. 5, 281–286 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Haass, C., Hung, A. Y., Selkoe, D. J. & Teplow, D. B. Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid β-protein precursor. J. Biol. Chem. 269, 17741–17748 (1994).

    CAS  PubMed  Google Scholar 

  11. 11

    Watson, D. J., Selkoe, D. J. & Teplow, D. B. Effects of the amyloid precursor protein Glu693→ Gln 'Dutch' mutation on the production and stability of amyloid β-protein. Biochem. J. 340, 703–709 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Walsh, D. M., Lomakin, A., Benedek, G. B., Condron, M. M. & Teplow, D. B. Amyloid β-protein fibrillogenesis–detection of protofibrillar intermediate. J. Biol. Chem. 272, 22364–22372 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Walsh, D. M., Hartley, D. M., Condron, M. M., Selkoe, D. J. & Teplow, D. B. In vitro studies of amyloid β-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692→Gly) Alzheimer's disease. Biochem J. 355, 869–877 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Tagliavini, F. et al. A new βPP mutation related to hereditary cerebral haemorrhage. Alz. Report 2, S28 (1999).

    Google Scholar 

  15. 15

    Grabowski, T. J., Cho, H. S., Vonsattel, J. P. G., Rebeck, G. W. & Greenberg, S. M. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann. Neurol. 49, 697–705 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Hasegawa, K., Yamaguchi, I., Omata, S., Gejyo, F. & Naiki, H. Interaction between Aβ(1–42) and Aβ(1–40) in Alzheimer's β-amyloid fibril formation in vitro. Biochemistry 38, 15514–15521 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Teplow, D. B. Structural and kinetic features of amyloid β-protein fibrillogenesis. Amyloid 5, 121–142 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Harper, J. D., Lieber, C. M. & Lansbury P. T. Jr. Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-β protein. Chem. Biol. 4, 951–959 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Harper, J. D., Wong, S. S., Lieber, C. M. & Lansbury, P. T. Jr. Observation of metastable Aβ amyloid protofibrils by atomic force microscopy. Chem. Biol. 4, 119–125 (1997).

    CAS  Article  Google Scholar 

  20. 20

    Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448–6453 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Walsh, D. M. et al. Amyloid β-protein fibrillogenesis–structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 36, 25945–25952 (1999).

    Article  Google Scholar 

  22. 22

    Harper, J. D., Wong, S. S., Lieber, C. M. & Lansbury, P. T. Assembly of Aβ amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease. Biochemistry 38, 8972–8980 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Hartley, D. M. et al. Protofibrillar intermediates of amyloid β-protein induce acute eletrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19, 8876–8884 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Conway, K. A. et al. Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proc. Natl. Acad. Sci. USA 97, 571–576 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Kamino, K. et al. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am. J. Hum. Genet. 51, 998–1014 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Suzuki, N. et al. An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants. Science 264, 1336–1340 (1994).

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    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. Nat. Med. 3, 67–72 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Tamaoka, A. et al. Amyloid β protein in plasma from patients with sporadic Alzheimer's disease. J. Neurol. Sci. 15, 65–68 (1996).

    Article  Google Scholar 

  30. 30

    Iwatsubo, T. Amyloid β protein in plasma as a diagnostic marker for Alzheimer's disease. Neurobiol. Aging 19, 161–163 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Mayeux, R. et al. Plasma amyloid β-peptide 1–42 and incipient Alzheimer's disease. Ann. Neurol. 46, 412–416 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Selkoe, D. J. The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 8, 447–453 (1998).

    CAS  Article  Google Scholar 

  33. 33

    He, W. & Barrow, C.J. The Aβ 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater β-sheet forming and aggregation propensities in vitro than full-length Aβ. Biochemistry 38, 10871–10877 (1999).

    CAS  Article  Google Scholar 

  34. 34

    Tjernberg, L. O. et al. Arrest of β-amyloid fibril formation by a pentapeptide ligand. J. Biol. Chem. 271, 8545–8548 (1996).

    CAS  Article  Google Scholar 

  35. 35

    Soto, C., Kindy, M. S., Baumann, M. & Frangione, B. Inhibition of Alzheimer's amyloidosis by peptides that prevent β-sheet conformation. Biochem. Biophys. Res. Commun. 226, 672–680 (1996).

    CAS  Article  Google Scholar 

  36. 36

    Wilson, C. A., Doms, R. W. & Lee, V. M. Intracellular APP processing and Aβ production in Alzheimer disease. J. Neuropath. Experiment. Neurol. 58, 787–794 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Gouras, G. K. et al. Intraneuronal Aβ42 accumulation in human brain. Am. J. Pathol. 156, 15–20 (2000).

    CAS  Article  Google Scholar 

  38. 38

    Harper, J. D. & Lansbury, P. T. Jr. Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truth and physiological consequences of the time-dependent solubility of amyloid proteins. Annu. Rev. Biochem. 66, 385–407 (1997).

    CAS  Article  Google Scholar 

  39. 39

    Klein, W. L., Krafft, G. A. & Finch, C. E. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219–224 (2001).

    CAS  Article  Google Scholar 

  40. 40

    Forsell, L. & Lannfelt, L. Amyloid precursor protein mutation at codon 713 (Ala→Val) does not cause schizophrenia: non-pathogenic variant found at codon 705 (silent). Neurosci. Lett. 184, 90–93 (1995).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank G. Arnerup, R. Kaiser, L. Lilius, S. Petrén and D. Yager for scientific support, and L. Tjernberg and colleagues in our department for comments on the manuscript. The following foundations are acknowledged: the Swedish Society for Medical Research, Trygg-Hansa, Stiftelsen för Gamla tjänarinnor, Åke Wibergs stiftelse, Erik Rönnbergs Stiftelse, Stiftelsen Clas Groschinskys minnesfond, Artur Eriksson, Gun & Bertil Stohnes stiftelse, Loo and Hans Ostermans stiftelse för geriatrisk forskning, Ulf Widengrens Minnesfond, Swedish Society for Medicine, the Alzheimer Foundation, the Swedish Medical Research Council (project 10819) and the US National Institutes of Health (grants NS38328 and AG14366 to D.B.T.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Lars Lannfelt.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nilsberth, C., Westlind-Danielsson, A., Eckman, C. et al. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation. Nat Neurosci 4, 887–893 (2001). https://doi.org/10.1038/nn0901-887

Download citation

Further reading

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