Systemic catabolism of Alzheimer's Abeta40 and Abeta42.
To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid beta (Abeta), we labeled human Abeta40 (monomeric, with predominant unordered structure) and Abeta42 (mixture of monomers and oligomers in approximately 50:50 ratio, rich in beta-sheet conformation) with either Na(125)I or (125)I-tyramine cellobiose, also known as the cell-trapping ligand procedure, testing their blood clearance and organ uptake in B6SJLF1/J mice. Irrespective of the labeling protocol, the peptide conformation, and the degree of oligomerization, both Abeta40 and Abeta42 showed a short half-life of 2.5-3.0 min. The liver was the major organ responsible for plasma clearance, accounting for >60% of the peptide uptake, followed by the kidney. In vivo, hepatocytes captured >90% of the radiolabeled peptides which, after endocytosis, were preferentially catabolized and excreted into the bile. Biliary excretion of intact as well as partially degraded Abeta species became obviously relevant at doses above 10 microg. The use of biotin-labeled Abeta allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled Abeta demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of Abeta, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of Abeta but the little fluctuation observed with age and disease stages.
Department of Pathology, New York University School of Medicine, New York, New York 10016, USA. ghisoj01@popmail.med.nyu.edu
Jorge
J
Ghiso
Marcos
M
Shayo
Miguel
M
Calero
Douglas
D
Ng
Yasushi
Y
Tomidokoro
Samuel
S
Gandy
Agueda
A
Rostagno
Blas
B
Frangione
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D007457:Iodine Radioisotopes