Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism

Exp Neurol. 2001 Feb;167(2):385-92. doi: 10.1006/exnr.2000.7569.

Abstract

Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid beta (A beta), are considered to be central to the pathology of Alzheimer's disease (AD). Soluble A beta is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble A beta present in circulation can cross the blood-brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that A beta originating from circulation may contribute to vascular and parenchymal A beta deposition in AD. Enhancing of A beta catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble A beta. To launch A beta clearance we have exploited the A beta-degrading activity of diverse alpha 2-macroglobulin (alpha 2-M)-proteinase complexes. Complexes with trypsin, alpha-chymotrypsin, and bromelain strongly degrade (125)I-A beta 1--42 whereas complexes with endogenous proteinases, e.g., plasmin and prostate-specific antigen, were not effective. A beta degradation by the complexes was not inhibited by alpha 1-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for A beta degradation is its binding to specific binding sites in alpha 2-M that may direct A beta to the active site of the caged proteinase. Ex vivo, enhanced degradation of (125)I-A beta 1--42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers. These results suggest that up-regulation of A beta catabolism could probably reduce the risk of developing AD by preventing A beta accumulation in brain and vasculature.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Binding, Competitive / drug effects
  • Blood Proteins / drug effects
  • Blood Proteins / metabolism
  • Bromelains / metabolism
  • Bromelains / pharmacology
  • Chymotrypsin / metabolism
  • Chymotrypsin / pharmacology
  • Drug Combinations
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Macromolecular Substances
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Rutin / analogs & derivatives*
  • Rutin / pharmacology
  • Trypsin / metabolism
  • Trypsin / pharmacology
  • alpha-Macroglobulins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Blood Proteins
  • Drug Combinations
  • Macromolecular Substances
  • Peptide Fragments
  • Phlogenzym
  • alpha-Macroglobulins
  • amyloid beta-protein (1-42)
  • Rutin
  • Bromelains
  • Chymotrypsin
  • alpha-chymotrypsin
  • Trypsin