Somatostatin, an In Vivo Binder to Aβ Oligomers, Binds to βPFOAβ(1-42) Tetramers

Abstract

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 (Aβ), and it binds to Aβ oligomers in vivo. Recently, the 3D structure of a membrane-associated β-sheet pore-forming tetramer (βPFO_Aβ(1-42) tetramer) has been reported. Here, we show that SST14 binds selectively to the βPFO_Aβ(1-42) tetramer with a K_D value of ∼40 μM without binding to monomeric Aβ(1-42). Specific NMR chemical shift perturbations, observed during titration of SST14, define a binding site in the βPFO_Aβ(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 βPFO_Aβ(1-42) tetramer as a relevant aggregation form of Aβ and as a potential target for AD.

Keywords: Alzheimer’s disease; Amyloid beta peptide; NMR spectroscopy; Native mass spectrometry; Protein−protein interactions; Somatostatin.