INHIBITION OF ALPHA(2)-MACROGLOBULIN PROTEINASE-MEDIATED DEGRADATION OF AMYLOID-BETA PEPTIDE BY APOLIPOPROTEIN-E AND ALPHA(1)-ANTICHYMOTRYPSIN - EVIDENCE THAT THE ALPHA(2)-MACROGLOBULIN/PROTEINASE COMPLEX MEDIATES DEGRADATION OF THE A-BETA PEPTIDE/

The soluble amyloid beta-peptide (A beta), is produced from the amyloi d beta-protein precursor (A beta PP) during normal cellular metabolism . The accumulation and deposition of extracellular A beta in senile pl aques, a characteristic neuropathological feature of Alzheimer's disea se (AD), may occur as a result of increased A beta synthesis or decrea sed degradation/clearance, or both. We now report that trypsin-activat ed alpha(2)-macroglobulin (alpha(2)M-T), efficiently degrades A beta i n vitro. Moreover, incubation of A beta with alpha(2)M-T prevents the in vitro formation of Thioflavine-S positive A beta fibrils as well as A beta-induced toxicity of cultured human cortical neuronal (HCN-1A) cells. Two senile plaque-associated proteins, apolipoprotein E (apoE) and alpha(1)-antychymotrypsin (ACT), markedly inhibit alpha(2)M-T-medi ated A beta degradation by a process that does not involve inhibition of the alpha(2)M-T catalytic site. Thus, the degradation and clearance of A beta by alpha(2)M-T may be impaired by the amyloid-promoting fac tors, apoE and ACT, both of which have been shown to be elevated in AD brain adn to be possible genetic risk factors for AD.