Zinc-Dependent Activation of the Plasma Kinin-Forming Cascade by Aggregated β Amyloid Protein

β Amyloid proteins (Aβ) of 38, 40, and 42 amino acids long were assessed for their ability to activate the plasma kinin-forming cascadein vitro.Incubation with a mixture of Factor XII (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 XII was omitted. There was rapid generation of bradykinin equal to the molar HK input indicating complete cleavage. Incubation of aggregated Aβ with diluted human plasma also led to prekallikrein activation and HK cleavage. Activation of the cascade by Aβ (1-38) was dependent upon its preincubation time in buffer, suggesting that aggregation of Aβ is required, and studies with Aβ (1-40) revealed time-dependent aggregation by microscopy and augmented zinc-dependent binding of both Factor XII and HK to aggregated Aβ. These data demonstrate that aggregated Aβ 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.