Aβ42 assembles into specific β-barrel pore-forming oligomers in membrane-mimicking environments

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.