Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments.
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.
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain;
Montserrat
M
Serra-Batiste
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain;
Martí
M
Ninot-Pedrosa
Biochemistry, Molecular, and Structural Biology Section, University of Leuven, Leuven 3001, Belgium;
Mariam
M
Bayoumi
NMR Facility, Scientific and Technological Centers, University of Barcelona, 08028 Barcelona, Spain;
Margarida
M
Gairí
Biochemistry, Molecular, and Structural Biology Section, University of Leuven, Leuven 3001, Belgium; Groningen Biomolecular Sciences & Biotechnology Institute, University of Groningen, 9747 AG, Groningen, The Netherlands.
Giovanni
G
Maglia
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; natalia.carulla@irbbarcelona.org.
Natàlia
N
Carulla
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002462:Cell Membrane / Q000737:chemistry*; D003902:Detergents / Q000494:pharmacology; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry*; D008823:Micelles; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D003902:Detergents; D008051:Lipid Bilayers; D008823:Micelles; D010767:Phosphorylcholine; C028810:dodecylphosphocholine; D004134:Dimyristoylphosphatidylcholine
Alzheimer’s disease; amyloid-β peptide; membrane pore; oligomer