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Edited by Christopher M. Dobson, University of Cambridge, Cambridge, United Kingdom, and approved August 2, 2016 (received for review April 7, 2016)
Significance
Numerous reports indicate that amyloid-β peptide (Aβ) oligomers, considered the pathogenic molecular form of Aβ in Alzheimer´s disease (AD), exert their neurotoxicity within the membrane. Therefore, it is critical to characterize them in such an environment. Here, we worked with two major Aβ variants and handled them as if they were membrane proteins. By doing so, we found that the Aβ variant most strongly linked to AD assembled into stable Aβ oligomers that adopted a specific structure and incorporated into membranes as pores, a feature linked to neurotoxicity. Having access to pore-forming Aβ oligomers with such a specific structure offers unique opportunities to fully characterize them and establish their involvement in AD.
Abstract
The formation of amyloid-β peptide (Aβ) 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 Aβ variants, Aβ40 and Aβ42. Accordingly, various types of detergent micelles were extensively screened to identify one that preserved the properties of Aβ in lipid environments—namely the formation of oligomers that function as pores. Remarkably, under the optimized detergent micelle conditions, Aβ40 and Aβ42 showed different behavior. Aβ40 aggregated into amyloid fibrils, whereas Aβ42 assembled into oligomers that inserted into lipid bilayers as well-defined pores and adopted a specific structure with characteristics of a β-barrel arrangement that we named β-barrel pore-forming Aβ42 oligomers (βPFOsAβ42). Because Aβ42, relative to Aβ40, has a more prominent role in AD, the higher propensity of Aβ42 to form βPFOs constitutes an indication of their relevance in AD. Moreover, because βPFOsAβ42 adopt a specific structure, this property offers an unprecedented opportunity for testing a hypothesis regarding the involvement of βPFOs and, more generally, membrane-associated Aβ oligomers in AD.
Footnotes
- ↵1To whom correspondence should be addressed. Email: natalia.carulla{at}irbbarcelona.org.
Author contributions: M.S.-B., M.N.-P., M.B., G.M., and N.C. designed research; M.S.-B., M.N.-P., and M.B. performed research; M.G. contributed new reagents/analytic tools; M.S.-B., M.N.-P., M.B., G.M., and N.C. analyzed data; and N.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1605104113/-/DCSupplemental.
Freely available online through the PNAS open access option.
Aβ42 β-barrel pore-forming oligomers
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