Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo.
Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-beta (Abeta) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Abeta indicate dysregulation of production or clearance of Abeta. Whether dysregulation of Abeta 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 Abeta 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.
Bateman
Randall J
RJ
Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, Missouri 63110, USA. batemanr@neuro.wustl.edu
Munsell
Ling Y
LY
Morris
John C
JC
Swarm
Robert
R
Yarasheski
Kevin E
KE
Holtzman
David M
DM
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000134:cerebrospinal fluid* / Q000378:metabolism*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D015415:Biomarkers