A?42 assembles into specific ?-barrel pore-forming oligomers in membrane-mimicking environments.

ABSTRACT: The formation of amyloid-? peptide (A?) 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? variants, A?40 and A?42. Accordingly, various types of detergent micelles were extensively screened to identify one that preserved the properties of A? in lipid environments-namely the formation of oligomers that function as pores. Remarkably, under the optimized detergent micelle conditions, A?40 and A?42 showed different behavior. A?40 aggregated into amyloid fibrils, whereas A?42 assembled into oligomers that inserted into lipid bilayers as well-defined pores and adopted a specific structure with characteristics of a ?-barrel arrangement that we named ?-barrel pore-forming A?42 oligomers (?PFOsA?42). Because A?42, relative to A?40, has a more prominent role in AD, the higher propensity of A?42 to form ?PFOs constitutes an indication of their relevance in AD. Moreover, because ?PFOsA?42 adopt a specific structure, this property offers an unprecedented opportunity for testing a hypothesis regarding the involvement of ?PFOs and, more generally, membrane-associated A? oligomers in AD.

SUBMITTER: Serra-Batiste M 

PROVIDER: S-EPMC5047179 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature