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

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.

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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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Correspondence to Randall J Bateman.

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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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