期刊
CHEMICAL SCIENCE
卷 12, 期 20, 页码 6896-6907出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0sc06426b
关键词
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资金
- BBSRC [BB/M023877/1]
- Chinese Scholarship Council (CSC)
- EMBO (Installation Grant)
- European Union under the European Regional Development Fund
- Regenerative Mechanisms for Health-ReMedy [MAB/20172]
- BBSRC [BB/M023877/1] Funding Source: UKRI
Aβ assemblies have been shown to bind to lipid bilayers, disrupting membrane integrity and potentially leading to Alzheimer's disease. Different forms of Aβ interact with membranes in varying ways, with oligomers and curvilinear protofibrils forming networks on the upper-leaflet of the bilayer, while monomeric and fibrillar Aβ have less impact. Incorporation of Aβ oligomers and protofibrils into lipid bilayers suggests a mechanism for membrane integrity loss.
Amyloid-beta (A beta) assemblies have been shown to bind to lipid bilayers. This can disrupt membrane integrity and cause a loss of cellular homeostasis, that triggers a cascade of events leading to Alzheimer's disease. However, molecular mechanisms of A beta cytotoxicity and how the different assembly forms interact with the membrane remain enigmatic. Here we use cryo-electron tomography (cryoET) to obtain three-dimensional nano-scale images of various A beta assembly types and their interaction with liposomes. A beta oligomers and curvilinear protofibrils bind extensively to the lipid vesicles, inserting and carpeting the upper-leaflet of the bilayer. A beta oligomers concentrate at the interface of vesicles and form a network of A beta-linked liposomes, while crucially, monomeric and fibrillar A beta have relatively little impact on the membrane. Changes to lipid membrane composition highlight a significant role for GM1-ganglioside in promoting A beta-membrane interactions. The different effects of A beta assembly forms observed align with the highlighted cytotoxicity reported for A beta oligomers. The wide-scale incorporation of A beta oligomers and curvilinear protofibrils into the lipid bilayer suggests a mechanism by which membrane integrity is lost.
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