Non-Esterified Fatty Acids Generate Distinct Low-Molecular Weight Amyloid-[beta]

Amyloid-[beta] (A[beta]) 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 A[beta] are increasingly believed to be the primary neurotoxic agents responsible for memory impairment....

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Bibliographic Details
Published in:PloS one 2011-04, Vol.6 (4), p.e18759
Main Authors: Kumar, Amit, Bullard, Rebekah L, Patel, Pritesh, Paslay, Lea C, Singh, Dipti, Bienkiewicz, Ewa A, Morgan, Sarah E, Rangachari, Vijayaraghavan
Format: Article
Language:English
Subjects:
Alzheimer's disease
Development and progression
Fatty acids
Oligomers
Peptides
Physiological aspects
Surface active agents
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Summary:Amyloid-[beta] (A[beta]) 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 A[beta] are increasingly believed to be the primary neurotoxic agents responsible for memory impairment. Anionic interfaces are known to influence the A[beta] aggregation process significantly. Here, we report the effects of interfaces formed by medium-chain (C9-C12), saturated non-esterified fatty acids (NEFAs) on A[beta]42 aggregation. NEFAs uniquely affected A[beta]42 aggregation rates that depended on both the ratio of A[beta]: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 A[beta]42 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 A[beta] aggregation in physiological lipid-rich environments, and (ii) reiterate the fact that all oligomeric forms of A[beta] need not be obligatory intermediates of the fibril formation pathway.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0018759