alpha 2-Macroglobulin-mediated degradation of amyloid beta 1-42: A mechanism to enhance amyloid beta catabolism

Peptides derived from proteolytic degradation of the amyloid precursor prot ein, e.g., amyloid beta (A beta), are considered to be central to the patho logy of Alzheimer's disease (AD). Soluble A beta is present in measurable c oncentrations 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 tha t A beta originating from circulation may contribute to vascular and parenc hymal A beta deposition in AD. Enhancing of A beta catabolism mediated by p roteolytic degradation or receptor-mediated endocytosis could be a key mech anism to maintain low concentrations of soluble A beta. To launch A beta cl earance we have exploited the A beta -degrading activity of diverse alpha2- macroglobulin (alpha2-M)-proteinase complexes. Complexes with trypsin, alph a -chymotrypsin, and bromelain strongly degrade I-125-A beta1-42 whereas co mplexes with endogenous proteinases, e.g., plasmin and prostate-specific an tigen, were not effective. A beta degradation by the complexes was not inhi bited by alpha1-antichymotrypsin and soybean trypsin inhibitor which normal ly would inactivate the free serine proteinases. A prerequisite for A beta degradation is its binding to specific binding sites in alpha2-M that may d irect A beta to the active site of the caged proteinase, Ex vivo enhanced d egradation of I-125-A beta1-42 in blood could be achieved upon oral adminis tration of high doses of proteinases to volunteers, These results suggest t hat up-regulation of Ap catabolism could probably reduce the risk of develo ping AD by preventing A beta accumulation in brain and vasculature. (C) 200 1 Academic Press.