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

beta Amyloid proteins (A beta) of 38, 40, and 42 amino acids long were assessed for their ability to activate the plasma kinin-forming cascade in vitro. 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 Factor MI was omitted. There was rapid generation of bradykinin equal to the molar HK input indicating complete cleavage. Incubation of aggregated A beta with diluted human plasma also led to prekallikrein activation and HK cleavage. Activation of the cascade by A beta (1-38) was dependent upon its preincubation time in buffer, suggesting that aggregation of A beta is required, and studies with A beta (1-40) revealed time-dependent aggregation by microscopy and augmented zinc-dependent binding of both Factor MI and HK to aggregated A beta. These data demonstrate that aggregated A beta can bind and activate proenzymes of the plasma kinin-forming cascade in a zinc-dependent reaction to release bradykinin and is of sufficient potency to do so at physiologic concentrations of each protein and in the presence of naturally occurring protease inhibitors. (C) 1999 Academic Press.