{"title":"Membrane-assisted Aβ40 aggregation pathways.","authors":"Fidha Nazreen Kunnath Muhammedkutty, Huan-Xiang Zhou","doi":"10.1016/j.xcrp.2025.102436","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here, we used extensive molecular dynamics (MD) simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β sheet (residues Q15-D23) and a bent β sheet (residues A30-V36). This work presents a comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.</p>","PeriodicalId":9703,"journal":{"name":"Cell Reports Physical Science","volume":"6 2","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905421/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Physical Science","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.xcrp.2025.102436","RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here, we used extensive molecular dynamics (MD) simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β sheet (residues Q15-D23) and a bent β sheet (residues A30-V36). This work presents a comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.
期刊介绍:
Cell Reports Physical Science, a premium open-access journal from Cell Press, features high-quality, cutting-edge research spanning the physical sciences. It serves as an open forum fostering collaboration among physical scientists while championing open science principles. Published works must signify significant advancements in fundamental insight or technological applications within fields such as chemistry, physics, materials science, energy science, engineering, and related interdisciplinary studies. In addition to longer articles, the journal considers impactful short-form reports and short reviews covering recent literature in emerging fields. Continually adapting to the evolving open science landscape, the journal reviews its policies to align with community consensus and best practices.