Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-Fibrillar Aggregates in Interfacial Environments

Authors

Amit Kumar, University of Southern MississippiFollow
Lea C. Paslay, University of Southern MississippiFollow
Daniel Lyons, University of Mississippi Medical Center
Sarah E. Morgan, University of Southern MississippiFollow
John J. Correia, University of Mississippi Medical CenterFollow
Vijayaraghavan Rangachari, University of Southern MississippiFollow

Document Type

Article

Publication Date

6-1-2012

Department

Chemistry and Biochemistry

Abstract

Aggregates of amyloid-β (Aβ) peptides have been implicated in the etiology of Alzheimer disease. Among the different forms of Aβ aggregates, low molecular weight species ranging between ∼2- and 50-mers, also called “soluble oligomers,” have emerged as the species responsible for early synaptic dysfunction and neuronal loss. Emerging evidence suggests that the neurotoxic oligomers need not be formed along the obligatory nucleation-dependant fibril formation pathway. In our earlier work, we reported the isolation of one such “off-pathway” 12–18-mer species of Aβ42 generated from fatty acids called large fatty acid-derived oligomers (LFAOs) (Kumar, A., Bullard, R. L., Patel, P., Paslay, L. C., Singh, D., Bienkiewicz, E. A., Morgan, S. E., and Rangachari, V. (2011) PLoS One 6, e18759). Here, we report the physiochemical aspects of LFAO-monomer interactions as well as LFAO-LFAO associations in the presence of interfaces. We discovered that LFAOs are a replicating strain of oligomers that recruit Aβ42 monomers and quantitatively convert them into LFAO assemblies at the expense of fibrils, a mechanism similar to prion propagation. We also found that in the presence of hexane-buffer or chloroform-buffer interfaces LFAOs are able to associate with themselves to form larger but non-fibrillar aggregates. These results further support the hypothesis that low molecular weight oligomers can be generated via non-fibril formation pathways. Furthermore, the unique replicating property of off-pathway oligomers may hold profound significance for Alzheimer disease pathology.

Comments

Publisher Version

Publication Title

Journal of Biological Chemistry

Volume

287

Issue

25

First Page

21253

Last Page

21264

Recommended Citation

Kumar, A., Paslay, L. C., Lyons, D., Morgan, S. E., Correia, J. J., Rangachari, V. (2012). Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-Fibrillar Aggregates in Interfacial Environments. Journal of Biological Chemistry, 287(25), 21253-21264.
Available at: https://aquila.usm.edu/fac_pubs/8871