期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 39, 页码 10866-10871出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1605104113
关键词
Alzheimer's disease; amyloid-beta peptide; membrane pore; oligomer
资金
- Severo Ochoa Award of Excellence from Ministerio de Economia y Competitividad (MINECO) (Government of Spain)
- MI NECO-Fondo Europeo de Desarrollo Regional (FEDER) Formacion de Personal Investigador (FPI) Program [SAF2012-35226, SAF2015-68789]
- Fundacio La Marato de TV3 Program Grant [20140730/31]
- Spanish Government program
The formation of amyloid-beta peptide (A beta) oligomers at the cellular membrane is considered to be a crucial process underlying neurotoxicity in Alzheimer's disease (AD). Therefore, it is critical to characterize the oligomers that form within a membrane environment. To contribute to this characterization, we have applied strategies widely used to examine the structure of membrane proteins to study the two major A beta variants, A beta 40 and A beta 42. Accordingly, various types of detergent micelles were extensively screened to identify one that preserved the properties of A beta in lipid environments-namely the formation of oligomers that function as pores. Remarkably, under the optimized detergent micelle conditions, A beta 40 and A beta 42 showed different behavior. A beta 40 aggregated into amyloid fibrils, whereas A beta 42 assembled into oligomers that inserted into lipid bilayers as well-defined pores and adopted a specific structure with characteristics of a beta-barrel arrangement that we named beta-barrel pore-forming A beta 42 oligomers (beta PFOsA beta 42). Because A beta 42, relative to A beta 40, has a more prominent role in AD, the higher propensity of A beta 42 to form beta PFOs constitutes an indication of their relevance in AD. Moreover, because beta PFOsA beta 42 adopt a specific structure, this property offers an unprecedented opportunity for testing a hypothesis regarding the involvement of beta PFOs and, more generally, membrane-associated A beta oligomers in AD.
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