Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease

• Published in: Biomimetics (Basel, Switzerland) Vol. 8; no. 6; p. 459
• Main Authors: Peng, Bushu, Xu, Shaoying, Liang, Yue, Dong, Xiaoyan, Sun, Yan
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.10.2023; MDPI
• Subjects: Alzheimer's disease; amyloid β−protein; Amyloidosis; Bacteria; Bacterial proteins; Beta protein; Biofilms; Brain stem; Disease; Electrostatic properties; Equilibrium; Glycoproteins; Health aspects; Hydrophobicity; Intestinal microflora; Microbiota; Microscopy; molecular dynamics simulation; molecular interactions; Neurodegenerative diseases; Oligomers; Peptides; phenol soluble modulins; Phenols; Physiological aspects; Proteins; Seeds; Simulation; Type 2 diabetes; β-Amyloid; China; United States > US
• ISSN: 2313-7673; 2313-7673
• DOI: 10.3390/biomimetics8060459

Since the proposal of the brainstem axis theory, increasing research attention has been paid to the interactions between bacterial amyloids produced by intestinal flora and the amyloid β−protein (Aβ) related to Alzheimer’s disease (AD), and it has been considered as the possible cause of AD. Therefore, phenol−soluble modulin (PSM) α3, the most virulent protein secreted by Staphylococcus aureus, has attracted much attention. In this work, the effect of PSMα3 with a unique cross−α fibril architecture on the aggregation of pathogenic Aβ40 of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aβ40 in a concentration−dependent manner and changed the aggregation pathway to form granular aggregates. However, PSMα3 oligomers promoted the generation of the β−sheet structure, thus shortening the lag phase of Aβ40 aggregation. Moreover, the higher the cross−α content of PSMα3, the stronger the effect of the promotion, indicating that the cross−α structure of PSMα3 plays a crucial role in the aggregation of Aβ40. Further molecular dynamics (MD) simulations have shown that the Met1−Gly20 region in the PSMα3 monomer can be combined with the Asp1−Ala2 and His13−Val36 regions in the Aβ40 monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aβ40 from the α−helix to β−sheet structure. By contrast, PSMα3 oligomers mainly combined with the central hydrophobic core (CHC) and the C−terminal region of the Aβ40 monomer by weak H−bonding and hydrophobic interactions, which could not inhibit the transition to the β−sheet structure in the aggregation pathway. Thus, the research has unraveled molecular interactions between Aβ40 and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD−related pathogenic Aβ.