Somatostatin, An In Vivo Binder To A Beta Oligomers, Binds To Beta Pfpa Beta(1-42) Tetramers

Somatostatin (SST14) is strongly related to Alzheimer's disease (AD), as its levels decline during aging, it regulates the proteolytic degradation of the amyloid beta peptide (A beta), and it binds to A beta oligomers in vivo. Recently, the 3D structure of a membrane-associated beta-sheet pore-forming tetramer (beta PFO A beta(1-42) tetramer) has been reported. Here, we show that SST14 binds selectively to the beta PFOA beta(1-42) tetramer with a K-D value of similar to 40 mu M without binding to monomeric A beta(1-42). Specific NMR chemical shift perturbations, observed during titration of SST14, define a binding site in the beta PFOA beta(1-42) tetramer and are in agreement with a 2:1 stoichiometry determined by both native mass spectroscopy and isothermal titration calorimetry. These results enabled us to perform driven docking and model the binding mode for the interaction. The present study provides additional evidence on the relation between SST14 and the amyloid cascade and positions the beta PFOA beta(1-42) tetramer as a relevant aggregation form of A beta and as a potential target for AD.