Investigating the Interactions of a Cyclic Peptide Hormone Somatostatin and Its Derivatives on Amyloid-Beta...

We investigated the effects of cyclic peptides somatostatin, its isomer d-Trp8-somatostatin, and marketed somatostatin derivatives octreotide and lanreotide on Aβ42 aggregation and cytotoxicity in mouse hippocampal HT22 cells. The aggregation kinetic studies show that all the cyclic peptides were able to reduce Aβ42 fibrillogenesis at 1, 5, 10, and 25 μM. The native cyclic peptide somatostatin exhibited superior inhibition compared to other cyclic peptides (91% inhibition at 25 μM) and exhibited greater inhibition compared to the reference agent orange G (86% inhibition at 25 μM), whereas the corresponding isomer d-Trp8-somatostatin exhibited 74% inhibition at 25 μM. The marketed drugs octreotide and lanreotide exhibited a similar inhibition profile (∼54% inhibition at 25 μM). Electron microscopy and immunoblotting experiments also demonstrate their antiaggregation properties. Furthermore, the cyclic peptides were not toxic to mouse hippocampal neuronal HT22 cells and exhibited cell viability ranging from 89 to 98.7% at 10 μM. Strikingly, the cyclic peptides somatostatin, d-Trp8-somatostatin, octreotide, and lanreotide were able to rescue mouse hippocampal neuronal HT22 cells from Aβ42-mediated cytotoxicity (cell viability: 71.7-83.8% at 10 μM). The marketed cyclic peptide drugs octreotide and lanreotide exhibited superior activity (cell viability: 83.8% and 81%, respectively) in preventing Aβ42-induced cytotoxicity compared to somatostatin and d-Trp8-somatostatin. Computational studies were able to identify the potential interaction sites of cyclic peptides in the Aβ42 hexamer assembly. Our studies demonstrate the ability of these cyclic peptides to interact with Aβ42 and reduce Aβ42-induced toxicity, highlighting the potential of marketed drugs octreotide and lanreotide in drug repurposing for Alzheimer's disease.