Abstract
Amyloid-β (Aβ) peptide aggregation is known to play a central role in the etiology of Alzheimer’s disease (AD). Among various aggregates, low-molecular weight soluble oligomers of Aβ are increasingly believed to be the primary neurotoxic agents responsible for memory impairment. Anionic interfaces are known to influence the Aβ aggregation process significantly. Here, we report the effects of interfaces formed by medium-chain (C9–C12), saturated non-esterified fatty acids (NEFAs) on Aβ42 aggregation. NEFAs uniquely affected Aβ42 aggregation rates that depended on both the ratio of Aβ:NEFA as well the critical micelle concentration (CMC) of the NEFAs. More importantly, irrespective of the kind of NEFA used, we observed that two distinct oligomers, 12–18 mers and 4–5 mers were formed via different pathway of aggregation under specific experimental conditions: (i) 12–18 mers were generated near the CMC in which NEFAs augment the rate of Aβ42 aggregation towards fibril formation, and, (ii) 4–5 mers were formed above the CMC, where NEFAs inhibit fibril formation. The data indicated that both 12–18 mers and 4–5 mers are formed along an alternate pathway called ‘off-pathway’ that did not result in fibril formation and yet have subtle structural and morphological differences that distinguish their bulk molecular behavior. These observations, (i) reflect the possible mechanism of Aβ aggregation in physiological lipid-rich environments, and (ii) reiterate the fact that all oligomeric forms of Aβ need not be obligatory intermediates of the fibril formation pathway.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline and memory impairment
Representative dotted lines for C9 shows the linear extrapolations of the curve to calculate critical micelle concentration (CMC), which is the point of intersection ; C) CMC of fatty acids determined by these measurements plotted as a function of carbon chain length. doi:10.1371/journal.pone.0018759.g001
In order to determine the respective CMCs of non-esterified fatty acids (NEFAs) in the buffer (10 mM Tris-HCl, 50 mM NaCl, pH 8.0) used in the study, we used N-phenyl-1-naphthylamine (NPN) as a probe that fluoresces upon binding to micelles, as reported earlier [40,45]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline and memory impairment. Aggregates from both pathways showed a bsheet conformation but differed in their ThT binding capability and morphology Prior to this observation, Barghorn and colleagues generated 38–48 kDa (8–12 mer) Ab42 oligomers, called ‘globulomers,’ by co-incubating Ab42 in low concentrations of SDS [32]. SDS is a good model system to mimic anionic lipid interfaces, it is not a physiological component and ambiguity would remain about the significance of its interaction with Ab. there is a need to explore whether physiological lipids and fatty acids can dictate similar multiple pathways of Ab aggregation and generate stable oligomers. The results indicate a fundamentally important phenomenon that has largely been overlooked, which may be a critical factor in AD pathogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
