Conformational Dynamics of Specific Aβ Oligomers Govern Their Ability to Replicate and Induce Neuronal Apoptosis
Document Type
Article
Publication Date
4-19-2016
Department
Chemistry and Biochemistry
School
Mathematics and Natural Sciences
Abstract
Oligomers of amyloid-β (Aβ) have emerged as the primary toxic agents responsible for early synaptic dysfunction and neuronal death in Alzheimer's disease (AD). Characterization of oligomers is an important step in the progress toward delineating the complex molecular mechanisms involved in AD pathogenesis. In our previous reports, we established that a distinct 12-24mer neurotoxic oligomer of Aβ42, called Large Fatty Acid derived Oligomers (LFAOs), exhibits a unique property of replication in which LFAOs directly duplicate to quantitatively larger amounts upon interacting with monomers. This self-propagative process of replication is somewhat reminiscent of prion propagation. In this report, we sought to investigate the concentration-dependent conformational dynamics LFAOs undergo and how such transitions manifest in their ability to replicate and induce neuronal apoptosis. The results indicate that LFAOs undergo a concentration-dependent transition between 12mers and disperse 12-24mers with a dissociation constant (Kd) of 0.1 μM. The two species differ in their respective tertiary/quaternary structures but not their secondary structures. This conformational dynamics of LFAOs correlates with their ability to replicate and to induce apoptosis in SH-SY5Y human neuroblastoma cells, with 12mers being more neurotoxic and prone to replication than 12-24mers. The latter result implicates the replication process dominates at low physiological concentrations. The observations made in this report may have profound significance in deciphering the elusive roles of Aβ oligomer phenotypes and in determining their prion-type behavior in AD pathology.
Publication Title
Biochemistry
Volume
55
Issue
15
First Page
2238
Last Page
2250
Recommended Citation
Dean, D. N.,
Pate, K. M.,
Moss, M. A.,
Rangachari, V.
(2016). Conformational Dynamics of Specific Aβ Oligomers Govern Their Ability to Replicate and Induce Neuronal Apoptosis. Biochemistry, 55(15), 2238-2250.
Available at: https://aquila.usm.edu/fac_pubs/16725