Neurodegenerative Dis 2004;1:231–235

Cerebrospinal Fluid Profile of Amyloid β Peptides in Patients with Alzheimer’s Disease Determined by Protein Biochip Technology

Maddalena A.S.a · Papassotiropoulos A.a · Gonzalez-Agosti C.a · Signorell A.a · Hegi T.b · Pasch T.b · Nitsch R.M.a · Hock C.a
aDivision of Psychiatry Research and bInstitute of Anesthesiology, University of Zürich, Zürich, Switzerland
email Corresponding Author

 goto top of outline Key Words

  • Alzheimer’s disease
  • β-Amyloid
  • Cerebrospinal fluid
  • Protein biochip

 goto top of outline Abstract

Amyloid-β peptides (Aβ) are major components of amyloid plaques in the Alzheimer’s disease (AD) brain and have been proposed as diagnostic markers in cerebrospinal fluid (CSF). Aβ derived from brain may be processed into fragments before emerging in CSF. Therefore, we determined mass profiles of Aβ peptides in CSF of patients with AD and age-matched healthy control subjects (CTR) by using protein biochip technology. Aβ peptides were captured on the chip surfaces (spots) by the specific monoclonal antibody 6E10 and were then analyzed by integrated surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS). We found Aβ species with mean molecular masses at 1,583.3 Da (corresponding to Aβ2–14), 2,068.5 Da (Aβ1–17), 2,166.4 Da (Aβ1–18), 3,676.6 Da (Aβ1–33), 3,789.4 Da (Aβ1–34), 4,076.9 Da (Aβ1–37), 4,134.0 Da (Aβ1–38), 4,233.3 Da (Aβ1–39), 4,332.4 Da (Aβ1–40) and 4,516.8 Da (Aβ1–42) in both AD (n = 24) and CTR (n = 24) subjects. Aβ1–38 appeared to be a major Aβ species in human CSF along with Aβ1–40. Quantitation revealed that CSF levels of Aβ1–38 were significantly decreased in AD as compared to CTR subjects. The CSF profile of Aβ peptides may be used for diagnostic and therapeutic purposes in clinical studies.

Copyright © 2004 S. Karger AG, Basel

 goto top of outline References
  1. Jarrett JT, Berger EP, Lansbury PT 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 1993;32:4693–4697.
  2. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y: 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 1994;13/1:45–53.
  3. Gravina SA, Ho L, Eckman CB, et al: Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem 1995;270:7013–7016.
  4. Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM: Progression of cerebral amyloid angiopathy: Accumulation of amyloid-beta40 in affected vessels. J Neuropathol Exp Neurol 1998;57:353–359.
  5. Boss MA: Diagnostic approaches to Alzheimer’s disease. Biochim Biophys Acta 2000;1502:188–200.
  6. Wiltfang J, Esselmann H, Bibl M, et al: Highly conserved and disease-specific patterns of carboxyterminally truncated Abeta peptides 1–37/38/39 in addition to 1–40/42 in Alzheimer’s disease and in patients with chronic neuroinflammation. J Neurochem 2002;81:481–496.
  7. Shoji M, Kanai M, Matsubara E, Tomidokoro Y, Shizuka M, Ikeda Y, Ikeda M, Harigaya Y, Okamoto K, Hirai S: The levels of cerebrospinal fluid Abeta40 and Abeta42(43) are regulated age-dependently. Neurobiol Aging 2001;22/2:209–215.
  8. Tapiola T, Pirttila T, Mikkonen M, et al: Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer’s disease. Neurosci Lett 2000;280/2:119–122.
  9. Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM: Plasma and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch Neurol 2000;57/1:100–105.
  10. Fukuyama R, Mizuno T, Mori S, Nakajima K, Fushiki S, Yanagisawa K: Age-dependent change in the levels of Abeta40 and Abeta42 in cerebrospinal fluid from control subjects, and a decrease in the ratio of Abeta42 to Abeta40 level in cerebrospinal fluid from Alzheimer’s disease patients. Eur Neurol 2000;43/3:155–160.
  11. Jensen M, Schroder J, Blomberg M, Engvall B, Pantel J, Ida N, Basun H, Wahlund LO, Werle E, Jauss M, Beyreuther K, Lannfelt L, Hartmann T: Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer’s disease and declines with disease progression. Ann Neurol 1999;45:504–511.
  12. Kanai M, Matsubara E, Isoe K, Urakami K, Nakashima K, Arai H, Sasaki H, Abe K, Iwatsubo T, Kosaka T, Watanabe M, Tomidokoro Y, Shizuka M, Mizushima K, Nakamura T, Igeta Y, Ikeda Y, Amari M, Kawarabayashi T, Ishiguro K, Harigaya Y, Wakabayashi K, Okamoto K, Hirai S, Shoji M: Longitudinal study of cerebrospinal fluid levels of tau, A beta1–40, and A beta1–42(43) in Alzheimer’s disease: A study in Japan. Ann Neurol 1998;44/1:17–26.
  13. Davies H, Lomas L, Austen B: Profiling of amyloid beta peptide variants using SELDI Protein Chip arrays. Biotechniques 1999;27:1258–1261.
  14. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM: The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport 1999;10:1699–1705.
  15. Austen BM, Frears ER, Davies H: The use of seldi proteinchip arrays to monitor production of Alzheimer’s betaamyloid in transfected cells. J Pept Sci 2000;6:459–469.
  16. Beher D, Wrigley JD, Owens AP, Shearman MS: Generation of C-terminally truncated amyloid-beta peptides is dependent on gamma-secretase activity. J Neurochem 2002;82:563–575.
  17. Lewczuk P, Esselmann H, Meyer M, Wollscheid V, Neumann M, Otto M, Maler JM, Ruther E, Kornhuber J, Wiltfang J: The amyloid-beta (Abeta) peptide pattern in cerebrospinal fluid in Alzheimer’s disease: Evidence of a novel carboxyterminally elongated Abeta peptide. Rapid Commun Mass Spectrom 2003;17:1291–1296.
  18. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
  19. World Health Organization G: ICD-10: The International Statistical Classification of Diseases and Related Health Problems, 10th revision. Geneva, World Health Organization, 1993.
  20. Wang R, Sweeney D, Gandy SE, Sisodia SS: The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry. J Biol Chem 1996;271:31894–31902.
  21. Kametani F, Nakamura Y, Tanaka K, Hashimoto R, Takeda M: Semiquantitative analysis of amyloid beta peptides using a combination of immunoprecipitation and matrix-assisted laser desorption ionization/time-of-flight-mass spectrometry. Anal Biochem 1999;275/2:262–265.
  22. Clarke NJ, Tomlinson AJ, Ohyagi Y, Younkin S, Naylor S: Detection and quantitation of cellularly derived amyloid beta peptides by immunoprecipitation-HPLC-MS. FEBS Lett 1998;430:419–423.
  23. Weggen S, Eriksen JL, Das P, et al: A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212–216.
  24. De Strooper B, Konig G: An inflammatory drug prospect. Nature 2001;414:159–160.

 goto top of outline Author Contacts

Christoph Hock, MD
Division of Psychiatry Research
Psychiatric University Hospital Zürich, Lenggstrasse 31
CH–8029 Zürich (Switzerland)
Tel. +41 44 384 2271, Fax +41 44 384 2275, E-Mail

 goto top of outline Article Information

Number of Print Pages : 5
Number of Figures : 3, Number of Tables : 1, Number of References : 24

 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 4-5, Year 2004 (Cover Date: Released November 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

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