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 neuropathological 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 trypsin-activated 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 amyloid-promoting 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.
- Aβ clearance
- Proteolytic degradation