Inhibition of α2-macroglobulin/proteinase-mediated degradation of amyloid β peptide by apolipoprotein E and α1-antichymotrypsin; Evidence that the α2-macroglobulin/proteinase complex mediates degradation of the Aβ peptide

Abstract

The soluble amyloid β–peptide (Aβ), is produced from the amyloid β-protein precursor (AβPP) during normal cellular metabolism. The accumulation and deposition of extracellular Aβ in senile plaques, a characteristic neumpathological feature of Alzheimer's disease (AD), may occur as a result of increased Aβ synthesis or decreased degradation/clearance, or both. We now report that trypsinactivated α2-macroglobulin (α2M-T), efficiently degrades Aβ in vitro. Moreover; incubation of Aβ with α2M-T prevents the in vitro formation of Thioflavine-S positive Aβ fibrils as well as Aβ-induced toxicity of cultured human cortical neuronal (HCN-IA) cells. Two senile plaque-associated proteins, apolipoprotein E (apoE) and α1-antichymotrypsin (ACT), markedly inhibit α2M-T-mediated Aβ degradation by a process that does not involve inhibition of the α2M-T catalytic site. Thus, the degradation and clearance of Aβ by α2M-T may be impaired by the amyloidpromoting factors, apoE and ACT, both of which have been shown to be elevated in AD brain and to be possible genetic risk factors for AD.