Systemic Catabolism of Alzheimer's Aβ40 and Aβ42

Abstract

To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid ␤ (A␤), we labeled human A␤40 (monomeric, with predominant unordered structure) and A␤42 (mixture of monomers and oligomers in ϳ50:50 ratio, rich in ␤-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 A␤40 and A␤42 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 A␤ species became obviously relevant at doses above 10 g. The use of biotin-labeled A␤ allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled A␤ demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of A␤, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of A␤ but the little fluctuation observed with age and disease stages. Alzheimer's disease (AD)1 is the most frequent type of amyloidosis in humans and the commonest form of clinical dementia. Extracellular A␤ amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma, being the cognitive areas the most severely affected. A␤, a 39 -42-amino acid-long peptide of unknown biological function, is an internal processing product of a larger type I transmembrane precursor molecule, APP, codified by a single multiexonic gene located on chromosome 21 (reviewed in Ref. 1). A soluble form of A␤ (sA␤) is present in the biological fluids of both normal individuals and AD patients as well as in cytosolic soluble fractions of normal, AD, and Down's syndrome brain homogenates (2-6). Notably, an increased amount of sA␤ has been reported in AD and Down's syndrome brain tissue in comparison to control individuals (7). Although the primary structures of deposited A␤ and sA␤ are indistinguishable, the circulating peptide is predominantly 40 residues long, whereas sA␤42, the major species in parenchymal deposits, is only a minor component of the circulating pool. To the present, it is not clear whether circulating sA␤s reflect systemic production, brain clearance, or both. The blood-brain barrier has the capability to modulate sA␤ brain uptake and clearance by controlling the uptake of circulating sA␤, either in its free form or bound to its transport apolipoproteins, as well as the elimination of brain-derived A␤ via transport-mediated clearance mechanisms (r...

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

“…Once A␤ is in the periphery, it is possible that A␤-specific IgGs form immune complexes more readily in plasma of certain AD patients compared with NDC (26). This could be because of higher levels of A␤ available for binding to antibodies or because of increased complement-mediated clearance of immune complexes (46,47). Our data confirm that certain peripheral plasma A␤ antibodies are complexed (Fig.…”

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…151,169 The liver appears to be the main organ responsible for this rapid clearance, followed by the kidney. 151 In vivo experiments indicate that hepatocytes are the main cell type within the liver responsible for Ab uptake and catabolism.…”

“…151 In vivo experiments indicate that hepatocytes are the main cell type within the liver responsible for Ab uptake and catabolism. 169 The molecular mechanisms that control hepatic clearance of Ab are not well characterized, however it is becoming clear that apoE and low-density LRP-1 are important mediators in this process.…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…The short half-life of circulating Ab (on the scale of minutes), 55,87 and the capacity of the liver to clear Ab at levels far exceeding its physiologic concentration in blood suggest that there is a biologic necessity to protect against elevations in circulating Ab. 87 This also suggests that rapid systemic clearance of Ab prevents reuptake by RAGE after efflux. Liver ligation was shown to be an effective method to maintain high levels of Ab in the circulation up to 1 hour after intravenous injection.…”