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

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. Therefo...

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Autores principales: Peng, Bushu, Xu, Shaoying, Liang, Yue, Dong, Xiaoyan, Sun, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604207/
https://www.ncbi.nlm.nih.gov/pubmed/37887589
http://dx.doi.org/10.3390/biomimetics8060459
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author Peng, Bushu
Xu, Shaoying
Liang, Yue
Dong, Xiaoyan
Sun, Yan
author_facet Peng, Bushu
Xu, Shaoying
Liang, Yue
Dong, Xiaoyan
Sun, Yan
author_sort Peng, Bushu
collection PubMed
description 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 Aβ(40) of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aβ(40) 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 Aβ(40) 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 Aβ(40). 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 Aβ(40) monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aβ(40) 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 Aβ(40) 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 Aβ(40) and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD−related pathogenic Aβ.
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spelling pubmed-106042072023-10-28 Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease Peng, Bushu Xu, Shaoying Liang, Yue Dong, Xiaoyan Sun, Yan Biomimetics (Basel) Article 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 Aβ(40) of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aβ(40) 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 Aβ(40) 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 Aβ(40). 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 Aβ(40) monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aβ(40) 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 Aβ(40) 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 Aβ(40) and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD−related pathogenic Aβ. MDPI 2023-10-01 /pmc/articles/PMC10604207/ /pubmed/37887589 http://dx.doi.org/10.3390/biomimetics8060459 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Peng, Bushu
Xu, Shaoying
Liang, Yue
Dong, Xiaoyan
Sun, Yan
Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease
title Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease
title_full Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease
title_fullStr Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease
title_full_unstemmed Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease
title_short Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease
title_sort effect of bacterial amyloid protein phenol−soluble modulin alpha 3 on the aggregation of amyloid beta protein associated with alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604207/
https://www.ncbi.nlm.nih.gov/pubmed/37887589
http://dx.doi.org/10.3390/biomimetics8060459
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