Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo

Nature Medicine volume 12, pages856–861(2006)Cite this article

Abstract

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-β (Aβ) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Aβ indicate dysregulation of production or clearance of Aβ. Whether dysregulation of Aβ synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Aβ in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.

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Figure 1: The amino acid sequence of Aβ is depicted in the amyloid precursor protein (APP) in the cell membrane with the leucines (L) labeled in red to indicate possible labeling sites.
Figure 2: Spectra of unlabeled and labeled Aβ17–28.
Figure 3: Diagram of in vivo human CNS protein labeling.
Figure 4: FSR and FCR of curves depicting labeled Aβ from three individuals with 9-h label infusion and 36-h sampling.

References

  1. 1

    Wolfe, R.R. Regulation of skeletal muscle protein metabolism in catabolic states. Curr. Opin. Clin. Nutr. Metab. Care 8, 61–65 (2005).

    CAS  Article  Google Scholar 

  2. 2

    San Pietro, A. & Rittenberg, D. A study of the rate of protein synthesis in humans. II. Measurement of the metabolic pool and the rate of protein synthesis. J. Biol. Chem. 201, 457–473 (1953).

    CAS  PubMed  Google Scholar 

  3. 3

    Yarasheski, K.E. Exercise, aging, and muscle protein metabolism. J. Gerontol. A Biol. Sci. Med. Sci. 58, M918–M922 (2003).

    Article  Google Scholar 

  4. 4

    Elias, N., Patterson, B.W. & Schonfeld, G. In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene. Arterioscler. Thromb. Vasc. Biol. 20, 1309–1315 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Owen, F. et al. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet 1, 51–52 (1989).

    CAS  Article  Google Scholar 

  6. 6

    Polymeropoulos, M.H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Podlisny, M.B., Lee, G. & Selkoe, D.J. Gene dosage of the amyloid beta precursor protein in Alzheimer's disease. Science 238, 669–671 (1987).

    CAS  Article  Google Scholar 

  9. 9

    Golde, T.E., Eckman, C.B. & Younkin, S.G. Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim. Biophys. Acta 1502, 172–187 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Selkoe, D.J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Gravina, S.A. et al. Amyloid beta protein (Abeta) in Alzheimer's disease brain. J. Biol. Chem. 270, 7013–7016 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Wisniewski, K.E., Wisniewski, H.M. & Wen, G.Y. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann. Neurol. 17, 278–282 (1985).

    CAS  Article  Google Scholar 

  13. 13

    Fishman, R.A. Cerebrospinal Fluid in Diseases of the Nervous System. (Saunders, Philadelphia, 1992).

    Google Scholar 

  14. 14

    Yarasheski, K.E. et al. Increased plasma gln and Leu Ra and inappropriately low muscle protein synthesis rate in AIDS wasting. Am. J. Physiol. 275, E577–E583 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Smith, Q.R., Momma, S., Aoyagi, M. & Rapoport, S.I. Kinetics of neutral amino acid transport across the blood-brain barrier. J. Neurochem. 49, 1651–1658 (1987).

    CAS  Article  Google Scholar 

  16. 16

    Wolfe, R.R., Chinkes, D.L. & Wolfe, R.R. Isotope Tracers In Metabolic Research: Principles and Practice of Kinetic Analysis. (Wiley-Liss, Hoboken, New Jersey, 2005).

    Google Scholar 

  17. 17

    Zlokovic, B.V. et al. Blood-brain barrier transport of circulating Alzheimer's amyloid beta. Biochem. Biophys. Res. Commun. 197, 1034–1040 (1993).

    CAS  Article  Google Scholar 

  18. 18

    DeMattos, R.B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 98, 8850–8855 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Poduslo, J.F., Curran, G.L., Wengenack, T.M., Malester, B. & Duff, K. Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's disease. Neurobiol. Dis. 8, 555–567 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Saido, T.C. Aβ Metabolism and Alzheimer's Disease. (Landes Bioscience, 2003).

    Google Scholar 

  21. 21

    Lanz, T.A., Hosley, J.D., Adams, W.J. & Merchant, K.M. Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo -6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575). J. Pharmacol. Exp. Ther. 309, 49–55 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Siemers, E. et al. Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin. Neuropharmacol. 28, 126–132 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Yarasheski, K.E., Smith, K., Rennie, M.J. & Bier, D.M. Measurement of muscle protein fractional synthetic rate by capillary gas chromatography/combustion isotope ratio mass spectrometry. Biol. Mass Spectrom. 21, 486–490 (1992).

    CAS  Article  Google Scholar 

  24. 24

    Merchak, A., Patterson, B.W., Yarasheski, K.E. & Hamvas, A. Use of stable isotope labeling technique and mass isotopomer distribution analysis of [(13)C]palmitate isolated from surfactant disaturated phospholipids to study surfactant in vivo kinetics in a premature infant. J. Mass Spectrom. 35, 734–738 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Garlick, P.J., McNurlan, M.A. & Preedy, V.R. A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of [3H]phenylalanine. Biochem. J. 192, 719–723 (1980).

    CAS  Article  Google Scholar 

  26. 26

    Cirrito, J.R. et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J. Neurosci. 23, 8844–8853 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Williams, M.A. Spinal catheter insertion via seated lumbar puncture using a massage chair. Neurology 58, 1859–1860 (2002).

    Article  Google Scholar 

  28. 28

    DeMattos, R.B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 98, 8850–8855 (2001).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the American Academy of Neurology Foundation, US National Institutes of Health (NIH) grants ADRC (P50 AG05681), GCRC (MO1 RR00036), Mass Spectrometry Resource (NIH RR000954), the Clinical Nutrition Research Unit (NIH DK056341) and The Alan A. and Edith L. Wolff Charitable Trust. We are grateful to the participants for their time and to Eli Lilly for providing m266 antibody.

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Affiliations

  1. Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    Randall J Bateman, John C Morris & David M Holtzman

  2. Department of the Alzheimer Disease Research Center, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    Randall J Bateman, John C Morris & David M Holtzman

  3. Department of Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    Randall J Bateman & David M Holtzman

  4. Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    Ling Y Munsell & Kevin E Yarasheski

  5. Departments of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    John C Morris

  6. Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    Robert Swarm

  7. Departments of Molecular Biology & Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, 63110, Missouri, USA

    David M Holtzman

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  1. Randall J Bateman
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  2. Ling Y Munsell
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Correspondence to Randall J Bateman.

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Competing interests

A provisional patent was filed by Washington University with Randall Bateman and David Holtzman as inventors on some of the methods described in this publication.

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Bateman, R., Munsell, L., Morris, J. et al. Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12, 856–861 (2006). https://doi.org/10.1038/nm1438

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