title: Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism.
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.
authors.affiliation: Institute of Biochemistry, University of Leipzig, Liebigstrasse 16, 04103 Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Lauer
authors.forename: A
authors.initials: A
authors.lastname: Reichenbach
authors.forename: G
authors.initials: G
authors.lastname: Birkenmeier
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D001963:Bromelains / Q000378:metabolism / Q000494:pharmacology; D002918:Chymotrypsin / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D046911:Macromolecular Substances; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D012431:Rutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014357:Trypsin / Q000378:metabolism / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001798:Blood Proteins; D004338:Drug Combinations; D046911:Macromolecular Substances; D010446:Peptide Fragments; C119937:Phlogenzym; D000511:alpha-Macroglobulins; C075222:amyloid beta-protein (1-42); D012431:Rutin; D001963:Bromelains; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D014357:Trypsin