Systemic catabolism of Alzheimer's Aβ40 and Aβ42

Jorge Ghiso, Marcos Shayo, Miguel Calero, Douglas Ng, Yasushi Tomidokoro, Samuel Gandy, Agueda Rostagno, Blas Frangione

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid β (Aβ), we labeled human Aβ40 (monomeric, with predominant unordered structure) and Aβ42 (mixture of monomers and oligomers in ∼50:50 ratio, rich in β-sheet conformation) with either Na125I or 125I-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 Aβ40 and Aβ42 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 Aβ species became obviously relevant at doses above 10 μg. The use of biotin-labeled Aβ allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled Aβ demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of Aβ, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of Aβ but the little fluctuation observed with age and disease stages.

Original languageEnglish
Pages (from-to)45897-45908
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number44
DOIs
StatePublished - 29 Oct 2004
Externally publishedYes

Fingerprint

Dive into the research topics of 'Systemic catabolism of Alzheimer's Aβ40 and Aβ42'. Together they form a unique fingerprint.

Cite this