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Article
Nature Medicine  2, 864 - 870 (1996)
doi:10.1038/nm0896-864

Secreted amyloid bold 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

D. Scheuner1, 16, 17, C. Eckman1, 2, 17, M. Jensen3, 17, X. Song4, 17, M. Citron5, N. Suzuki6, T.D. Bird7, 12, J. Hardy14, M. Hutton14, W. Kukull8, E. Larson9, L. Levy-Lahad9, 13, M. Viitanen3, E. Peskind10, 13, P. Poorkaj7, 13, G. Schellenberg7, 9, 11, 13, R. Tanzi15, W. Wasco15, L. Lannfelt3, D. Selkoe5 & S. Younkin2, 18

  1 Department of Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106, USA

  2Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida 32224, USA

  3Karolinska Institute, Department of Clinical Neurosdence and Family Medicine, Huddinge University Hospital, NovumKFC, S-141 86Huddinge, Sweden

  4Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA

  5Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

  6Discovery Research Division, Takeda Chemical Industries, Ltd., Wadai 10, 300-42 Tsukuba, Ibaraki, Japan

  7Department of Neurology, University of Washington, Seattle, Washington 98185, USA

  8Department of Epidemiology, University of Washington, Seattle, Washington 98185, USA

  9Department of Medicine, University of Washington, Seattle, Washington 98185, USA

  10Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98185, USA

  11Department of Pharmacology, University of Washington, Seattle, Washington 98185, USA

  12Neurology Service Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA

  13Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, USA

  14Suncoast Alzheimer's Disease Laboratories, Department of Psychiatry, University of South Florida, Tampa, Florida 33613, USA

  15Genetics and Aging Unit, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Charlestown, Massachusetts 02129, USA

  16D. Scheuner present address: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, USA

  17D.Scheuner, C.E., M.J. and X.S. contributed equally to this study.

  18Correspondence should be addressed to S.Y.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta−protein (Abeta) ending at Abeta42(43) in vivo, we performed a blinded comparison of plasma Abeta levels in carriers of these mutations and controls. Abeta1 −42(43) was elevated in plasma from subjects with FAD−linked PS1 (P < 0.0001), PS2 N141I (P = 0.009), APP K670N,M671L (P < 0.0001), and APP V717I (one subject) mutations. Abeta ending at Abeta42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or P52 (P = 0.03) mutations. These findings indicate that the FAD−linked mutations may all cause Alzheimer's disease by increasing the extracellular concentration of Abeta42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

REFERENCES
  1. Iwatsubo, T., Mann, D.M., Odaka, A., Suzuki, N. & Ihara, Y. Amyloid beta protein (Abeta) deposition: Abetap42(43) precedes Abeta40 in Down syndrome. Ann. Neurol. 37, 294−299 (1995). | PubMed  | ISI | ChemPort |
  2. Gravina, S.A. et al. Amyloid beta protein (Abeta) in Alzheimer's disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Abeta40 or Abeta42(43). J. Biol. Chem. 270, 7013−7016 (1995). | Article | PubMed  | ISI | ChemPort |
  3. Roher, A. et al. Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease. J. Biol. Chem. 268, 3072−3083 (1993). | PubMed  | ISI | ChemPort |
  4. Miller, D.L. et al. Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease. Arch. Biochem. 301, 41−52 (1993). | Article | PubMed  | ISI | ChemPort |
  5. Seubert, P. et al. Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature 359, 325−327 (1992). | ChemPort |
  6. Shoji, M. et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258, 126−129 (1992). | PubMed  | ISI | ChemPort |
  7. Haass, C. et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359, 322−325 (1992). | Article | PubMed  | ISI | ChemPort |
  8. Busciglio, J., Gabuzda, D.H., Matsudaira, P. & Yankner, B.A. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc. Natl. Acad. Sci. USA 90, 2092−2096 (1993). | PubMed  | ChemPort |
  9. Dovey, H.F., Suomesaari-Chrysler, S., Lieberburg, I., Sinha, S. & Kiem, P.S. Cells with a familial Alzheimer's disease mutation produce authentic beta-peptide. Neuro Report 4, 1039−1042(1993). | ChemPort |
  10. Vigo-Pelfrey, C., Lee, D., Keim, P., Lieberburg, I. & Schenk, D.B. Characterization of p amyloid peptide from human cerebrospinal fluid. J. Neurochem. 61, 19965−19968 (1993).
  11. Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C.L. & Beyreuther, K. Aggregation and secondary structure of synthetic amyloid betaA4 peptides of Alzheimer's disease. J. Mol. Biol. 218, 149−163 (1991). | PubMed  | ISI | ChemPort |
  12. Burdick, D. et al. Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. J. Biol. Chem. 267, 546−554 (1992). | PubMed  | ISI | ChemPort |
  13. Jarrett, J.T. & Lansbury, P.T., Seeding "one-dimensional crystallization" of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055−1058 (1993). | PubMed  | ISI | ChemPort |
  14. Jarrett, J.T., Berger, E.P. & Lansbury, P.T., The carboxy terminus of p amyloid protein is critical for the seeding of amyloid formation: Implications for patho-genesis of Alzheimer's disease. Biochemistry 32, 4693−4697 (1993). | PubMed  | ISI | ChemPort |
  15. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754−760 (1995). | Article | PubMed  | ISI | ChemPort |
  16. Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 973−977 (1995). | PubMed  | ChemPort |
  17. Levy-Lahad, E. et al. A familial Alzheimer's disease locus on chromosome 1. Science 269, 970−973 (1995). | PubMed  | ChemPort |
  18. Rogaev, E. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775−778 (1995). | Article | PubMed  | ISI | ChemPort |
  19. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704−706 (1991). | Article | PubMed  | ISI | ChemPort |
  20. Naruse, S. et al. Missense mutation Val-Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet 337, 978 (1991). | Article | PubMed  | ChemPort |
  21. Yoshioka, K., Miki, T., Katsuya, T., Ogihara, T. & Sakaki, Y. The 717Val-Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem. Biophys. Res. Commun. 178, 1141 (1991). | PubMed  | ChemPort |
  22. Hardy, J. et al. Molecular classification of Alzheimer's disease. Lancet 337, 1342 (1991). | PubMed  |
  23. Murrell, J., Farlow, M., Ghetti, B. & Benson, M.D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254, 97−99 (1991). | PubMed  | ISI | ChemPort |
  24. Chartier-Harlin, M.-C. et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353, 844−846 (1991). | Article | PubMed  | ChemPort |
  25. Mullan, M. et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nature Genet. 1, 345−347 (1992). | Article | PubMed  | ISI | ChemPort |
  26. Citron, M. et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc. Natl. Acad. Sci. USA 91, 11993−11997 (1994). | PubMed  | ChemPort |
  27. Cai, X.D., Golde, T.E. & Younkin, S.G. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259, 514−516 (1993). | PubMed  | ISI | ChemPort |
  28. Citron, M. et al. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases p-protein production. Nature 360, 672−674 (1992). | Article | PubMed  | ISI | ChemPort |
  29. Suzuki, N. et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (P APP717) mutants. Science 264, 1336−1340 (1994). | PubMed  | ISI | ChemPort |
  30. Tamaoka, A. et al. APP717 missense mutation affects the ratio of amyloid beta protein species (Abetal-42/43 and Abeta1-40) in familial Alzheimer's disease brain. J. Biol. Chem. 269, 32721−32724 (1994). | PubMed  | ISI | ChemPort |
  31. Motter, R. et al. Reduction of beta-amyloid peptide 42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann. Neurol. 38, 643−648 (1995). | PubMed  | ISI | ChemPort |
  32. Grubb, A. et al. Abnormal metabolism of gamma-trace alkaline microprotein. The basic defect in hereditary cerebral hemorrhage with amyloidosis. N. Engl. J. Med. 311, 1547−1549 (1984). | PubMed  | ISI | ChemPort |
  33. Ma, J., Yee, A., Brewer, H.B., Jr., Das, S. & Potter, H. Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372, 92−94 (1994). | Article | PubMed  | ISI | ChemPort |
  34. Wisniewski, T., Castano, E.M., Golabek, A., Vogel, T. & Frangione, B. Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. Am. J. Pathol. 145, 1030−1035 (1994). | PubMed  | ISI | ChemPort |
  35. Castaño, E. et al. Fibrillogenesis in Alzheimer's disease of the amyloid beta peptides and apolipoprotein E. Biochem. J. 306, 599−604 (1995). | PubMed  | ISI |
  36. Evans, K.C., Berger, E.P., Cho, C.G., Weisgraber, K.H. & Lansbury, P.T., Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: Implications for the pathogenesis and treatment of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 92, 763−767 (1995). | PubMed  | ChemPort |
  37. Larson, E.B. et al. University of Washington Alzheimer's Disease Patient Registry (ADPR): 1987−1988. Aging 2, 404−408 (1990). | PubMed  | ChemPort |
  38. Kukull, W.A. et al. Solvent exposure as a risk factor for Alzheimer's disease: A case-control study. Am. J. Epidemiol. 141, 1059−1071 (1995); (erratum) Am. J. Epidemiol. 142, 450 (1996). | PubMed  | ISI | ChemPort |
  39. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: Report of the NINCSDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34, 939−944 (1984). | PubMed  | ISI | ChemPort |
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ISSN: 1078-8956
EISSN: 1546-170X
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