Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a
mechanism to enhance amyloid beta catabolism.
Lauer D, Reichenbach A,
Birkenmeier G. 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.
Institute
of Biochemistry, University of Leipzig, Liebigstrasse 16, 04103.
Leipzig, Germany.
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.
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