Lauer D., Reichenbach A.*, Birkenmeier G.
Institute of Biochemistry, University of Leipzig, Germany; and *Paul-Flechsig-Institute for Brain Research, Department of Neurophysiology, University of Leipzig, Germany
Experimental Neurology (2001): 167, 385 – 392.
Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid b (Ab), are considered to be central to the pathology of Alzheimer’s disease (AD). Soluble Ab is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble Ab present in circulation can cross the blood-brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that Ab originating from circulation may contribute to vascular and parenchymal Ab deposition in AD. Enhancing of Ab catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble Ab. To launch Ab clearance we have exploited the Ab-degrading activity of diverse a2-macroglobulin (a2-M)-proteinase complexes. Complexes with trypsin, a-chymotrypsin, and bromelain strongly degrade 125I-Ab1-42 whereas complexes with endogenous proteinases, e.g., plasmin and prostate specific antigen, were not effective. Ab degradation by the complexes was not inhibited by al-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for Ab degradation is its binding to specific binding sites in a2-M that may direct Ab to the active site of the caged proteinase. Ex vivo, enhanced degradation of 125I-Ab1-42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers. These results suggest that up-regulation of Ab catabolism could probably reduce the risk of developing AD by preventing Ab accumulation in brain and vasculature.
Key Words: Alzheimer’s disease; amyloid b; a2-macroglobulin; proteinase; proteinase inhibitor; oral enzyme therapy.
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