Zinc-dependent activation of the plasma kinin-forming cascade by aggregated beta amyloid protein

beta Amyloid proteins (A beta) of 38, 40, and 42 amino acids long were asse ssed for their ability to activate the plasma kinin-forming cascade in vitr o. Incubation with a mixture of Factor MI (Hageman Factor), prekallikrein, and high-molecular-weight kininogen (HK) led to conversion of prekallikrein to kallikrein that was dependent on zinc ion. No activation occurred if Fa ctor MI was omitted. There was rapid generation of bradykinin equal to the molar HK input indicating complete cleavage. Incubation of aggregated A bet a with diluted human plasma also led to prekallikrein activation and HK cle avage. Activation of the cascade by A beta (1-38) was dependent upon its pr eincubation time in buffer, suggesting that aggregation of A beta is requir ed, and studies with A beta (1-40) revealed time-dependent aggregation by m icroscopy and augmented zinc-dependent binding of both Factor MI and HK to aggregated A beta. These data demonstrate that aggregated A beta can bind a nd activate proenzymes of the plasma kinin-forming cascade in a zinc-depend ent reaction to release bradykinin and is of sufficient potency to do so at physiologic concentrations of each protein and in the presence of naturall y occurring protease inhibitors. (C) 1999 Academic Press.