Ganglioside Lipids Inhibit the Aggregation of the Alzheimer’s Related Peptide Amyloid-β

Author:

Toprakcioglu ZenonORCID,Jayaram Akhila K.,Knowles Tuomas P. J.ORCID

Abstract

AbstractThe aggregation of the amyloid-β(Aβ) peptides (Aβ42/Aβ40) into toxic amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimers disease (AD). While the molecular mechanisms behind this aggregation process are not fully known, it has been shown that some biomolecules can accelerate this process while others can inhibit amyloid formation. Lipids, which are ubiquitously found in cell membranes, play a pivotal role in protein aggregation. Here, we investigate how ganglioside lipids, which are abundant in the brain and in neurons, can influence the aggregation kinetics of both Aβ42 and Aβ40. We find that ganglioside lipids can drastically inhibit the aggregation of Aβ42, while in the case of the smaller peptide (Aβ40), gangliosides can completely inhibit the aggregation process. Moreover, through kinetic analysis we show that the primary nucleation rate is greatly affected by the addition of gangliosides, and that the presence of these lipids can inhibit the primary nucleation rate of Aβ42 by 3 orders of magnitude. By means of viability assays of neuroblastoma cells (SH-SY5Y), we further demonstrate that amyloid fibrils formed in the absence of gangliosides are more toxic to these cells than amyloid fibrils formed in the presence of gangliosides, elucidating the inhibitory and potentially protective role that these lipids can play. Additionally, we show that monomeric Aβ40/Aβ42 form complexes with gangliosides, but not with other lipids such as POPS, suggesting that formation of ganglioside-Aβcomplexes can act as a potential pathway towards inhibiting amyloid-βaggregation. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of Aβand shed light on the key factors that control these processes, especially in view of the fact that declining levels of gangliosides in neurons have been associated with ageing.

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Modulation of α-synuclein in vitro aggregation kinetics by its alternative splice isoforms;Proceedings of the National Academy of Sciences;2024-02-07

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3