Non-Esterified Fatty Acids Generate Distinct Low-Molecular Weight Amyloid-β (Aβ42) Oligomers along Pathway Different from Fibril Formation

Authors

Amit Kumar, University of Southern MississippiFollow
Rebekah L. Bullard, University of Southern MississippiFollow
Pritesh Patel, University of Southern Mississippi
Lea C. Paslay, University of Southern MississippiFollow
Dipti Singh, University of Southern Mississippi
Ewa A. Bienkiewicz, Florida State University
Sarah E. Morgan, University of Southern MississippiFollow
Vijayaraghavan Rangachari, University of Southern MississippiFollow

Document Type

Article

Publication Date

4-1-2011

Department

Chemistry and Biochemistry

Abstract

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.

Publication Title

PLoS ONE

Volume

6

Issue

4

Recommended Citation

Kumar, A., Bullard, R. L., Patel, P., Paslay, L. C., Singh, D., Bienkiewicz, E. A., Morgan, S. E., Rangachari, V. (2011). Non-Esterified Fatty Acids Generate Distinct Low-Molecular Weight Amyloid-β (Aβ42) Oligomers along Pathway Different from Fibril Formation. PLoS ONE, 6(4).
Available at: https://aquila.usm.edu/fac_pubs/8881