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    Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity

    Year: 2019

    Journal: Langmuir, Volume 35, 1-Dec, page 16024–16036

    Authors: Vander Zanden, Crystal M.; Warnkiler, Lois; Bowers, Isabella; Watkins, Erik B.; Majewski, Jaroslaw; Chi, Eva Y.

    Organizations: Division of Chemistry (CHE), National Science Foundation [NSF/CHE-1834750]; Division of Materials Research (DMR), National Science FoundationNational Science Foundation (NSF) [NSF/CHE-1834750]; U.S. DOEUnited States Department of Energy (DOE) [DE-AC02-06CH11357]; NSFNational Science Foundation (NSF) [1150855, 1605225, 1560058]; ASERT IRACDA [K12 GM088021]; UNMCCC [P30 CA118100]; UNM CTSC [UL1 TR001449]; NM INBRE [P20 GM103451]

    In Alzheimer's disease, the amyloid-beta peptide (A beta) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric A beta (A beta(m)) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally A beta(m). To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare A beta(m), FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All A beta species were highly surface active and rapidly adopted beta-sheet rich structures upon adsorption to the air/water interface. Likewise, all A beta species had affinity for the anionic membrane. A beta(m) rapidly converted to beta-sheet rich assemblies upon binding the membrane, and these aggregated structures of A beta(m) and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated A beta toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of A beta neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.
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