Prostaglandin E2 induced polymerization of human α-1-antichymotrypsin and suppressed its protease inhibitory activity:: Implications for Alzheimer's disease

Different molecular forms of a-l-antichymotrypsin (ACT) in sera and cerebrospinal fluids fi om patients with Alzheimer's disease (AD) were detected. Monomeric and polymeric ACT were observed by polyacrylamide gel electrophoresis of both sera and cerebrospinal fluids. ACT polymers were increased in AD patients with the apolipoprotein E (APOE) 4 allele. Increased levels of inactive ACT molecules were also detected in brain homogenates of patients with the APOE 4 allele. Experimental conditions promoting in vitro polymerization of ACT and the effect of polymerization on the biological activity of this serpin were also explored. Incubation of this serpin with prostaglandin of E series (PGE 2) induced ACT polymerization and decreased its activity. Amyloid beta-peptide(1-42) did not significantly affected the biological activity of ACT. Inactivation of protease inhibitors by inflammatory molecules such as PGE 2 released fi om activated microglia in AD brains may promote amyloid deposition and neurodegeneration. (C) 1998 Academic Press.