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 E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology

Nature Medicine volume 2, pages 1146–1150 (1996)Cite this article

Abstract

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early–onset familial Alzheimer's disease (FAD)1,2 and are associated with increased levels of amyloid β–peptides (Aβ) ending at residue 42 (Aβ42) in plasma and skin fibroblast media of gene carriers3. Aβ42 aggregates readily and appears to provide a nidus for the subsequent aggregation of Aβ40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1–FAD patients from a large Colombian kindred5 bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation2. Using antibodies specific to the alternative carboxy–termini of Aβ, we detected massive deposition of Aβ42, the earliest and predominant form of plaque Aβ to occur in AD (ref. 6–8), in many brain regions. Computer–assisted quantification revealed a significant increase in Aβ42, but not Aβ40, burden in the brains from 4 PS1–FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous Aβ42–reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased Aβ42 levels in PS1–FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the β–amyloid precursor protein at the C–terminus of Aβ to favor deposition of Aβ42

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

References

  1. Sherrington, R. et al. Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease. Nature 375, 754–760 (1995).

    Article  CAS  Google Scholar 

  2. Clark, R.F. et al. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature Genet. 11, 219–222 (1995).

    Article  CAS  Google Scholar 

  3. 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 

  4. Jarrett, J.T. & Lansbury, P.T. Jr. Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).

    Article  CAS  Google Scholar 

  5. Lopera, F. et al. Demencia tipo Alzheimer con agregación familiar en Antioquia, Colombia. Acta Neurol. Colombiana 10, 173–187 (1994).

    Google Scholar 

  6. Iwatsubo, T. et al. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron 13, 45–53 (1994).

    Article  CAS  Google Scholar 

  7. Iwatsubo, T., Mann, D.M., Odaka, A., Suzuki, N. & Ihara, Y. Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann. Neurol. 37, 294–299 (1995).

    Article  CAS  Google Scholar 

  8. Lemere, C.A. et al. Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3, 16–32 (1996).

    Article  CAS  Google Scholar 

  9. Yamaguchi, H., Sugihara, S., Ishiguro, K., Takashima, A. & Hirai, S. Immunohistochemical analysis of COOH-termini of amyloid beta protein (Aβ) using end-specific antisera for Aβ40 and Aβ42 in Alzheimer's disease and normal aging. Amyloid Int. J. Clin. Invest. 2, 7–16 (1995).

    CAS  Google Scholar 

  10. Saido, T.C. et al. Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(p3), in senile plaques. Neuron. 14, 457–466 (1995).

    Article  CAS  Google Scholar 

  11. Haltia, M. et al. Chromosome 14-encoded Alzheimer's disease: Genetic and clinicopathological description. Ann. Neurol. 36, 362–367 (1994).

    Article  CAS  Google Scholar 

  12. Lampe, T.H. et al. Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred. Ann. Neurol. 36, 368–378 (1994).

    Article  CAS  Google Scholar 

  13. Kovacs, D.M. et al. Alzheimer-associated presenilins 1 and 2: Neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Med. 2, 224–229 (1996).

    Article  CAS  Google Scholar 

  14. Schmechel, D.E. et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 9649–9653 (1993).

    Article  CAS  Google Scholar 

  15. Greenberg, S.M., Rebeck, G.W., Vonsattel, J.P.G., Gomez-Isla, T. & Hyman, B.T. Apolipoprotein E ɛ4 and cerebral hemorrhage associated with amyloid angiopathy. Ann. Neurol. 38, 254–259 (1995).

    Article  CAS  Google Scholar 

  16. Song, X.-H. et al. Plasma amyloid β protein (Aβ) is increased in carriers of familial AD (FAD) linked to chromosome 14. Soc. Neurosd. Abstr. 21, 1501 (1995).

    Google Scholar 

  17. Jarrett, J.T., Berger, E.P. & Lansbury, P.T. Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–4697 (1993).

    Article  CAS  Google Scholar 

  18. Tamaoka, A. et al. APP717 missense mutation affects the ratio of amyloid β protein species (Aβ1–42/43 and Aβ1–40) in familial Alzheimer's disease brain. J. Biol. Chem. 269, 32721–32724 (1994).

    CAS  Google Scholar 

  19. Mann, D.M.A. et al. Predominant deposition of amyloid-β42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am. J. Pathol. 148, 1257–1266 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Mann, D.M.A. et al. Amyloid β protein (Aβ) deposition in chromosome 14-linked Alzheimer's disease: Predominance of Aβ42(43). Ann. Neurol. 40, 149–156 (1996).

    Article  CAS  Google Scholar 

  25. Kosik, K.S. et al. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1, 817–825 (1988).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center For Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, LMRC 103b, 221 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Cynthia A. Lemere, Kenneth S. Kosik, Edward H. Koo & Dennis J. Selkoe

  2. Departments of Neurology, Biochemistry and Pathology, Universidad de Antioquia, Medellím, Colombia

    Francisco Lopera, Jorge Ossa, Andres Ruiz, Alonso Martinez, Lucia Madrigal, Liliana Hincapie, Juan Carlos Arango L. & Juan Carlos Arango V.

  3. Departments of Psychiatry and Genetics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA

    Corrine L. Lendon & Alison M. Goate

  4. Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Takaomi C. Saido

  5. College of Medical Care and Technology, Gunma University, Gunma, Japan

    Haruyasu Yamaguchi

  6. Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, LMRC 103b, 221 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Douglas C. Anthony & Edward H. Koo

Authors
  1. Cynthia A. Lemere
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco Lopera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth S. Kosik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Corrine L. Lendon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jorge Ossa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takaomi C. Saido
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haruyasu Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andres Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alonso Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lucia Madrigal
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Liliana Hincapie
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Juan Carlos Arango L.
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Douglas C. Anthony
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Edward H. Koo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Alison M. Goate
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Dennis J. Selkoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Juan Carlos Arango V.
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lemere, C., Lopera, F., Kosik, K. et al. The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat Med 2, 1146–1150 (1996). https://doi.org/10.1038/nm1096-1146

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1096-1146

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