One of the characteristics of Alzheimer's disease is the presence of neurotoxic deposits in brain tissues, which are largely made up of a short peptide referred to as A?. The elucidation of the factors responsible for the formation and stabilization of pathologically relevant fibrils is important for designing preventive and therapeutic agents to combat the disease.
We aim to investigate one specific aspect of the fibril stabilization process as part of the overall fibril stability picture, namely the role of individua non-polar side chains located in the hydrophobic interior of the fibrils. Thus, our studies will complement global investigations into stability by revealing the most important local sites, which can then become targets for the design of modifications, ligands, and mutants that disrupt the stabilization of the fibrils. Our tools will allow for a balanced view of kinetic and thermodynamic stabilization at the selected sites. We will study two different morphologies of the wild-type peptide as well as a mutant associated with the early onset of the disease. We will utilize deuterium nuclear magnetic resonance spectroscopy and computational modeling to achieve this goal.

Public Health Relevance

Alzheimer's disease is characterized by toxic deposits (plaques) in brain tissue. Our project investigates one of the mechanisms that may be involved in the stabilization and formation of these plaques. In particular, we will study how specific molecular segments may contribute to this process, which would be useful for the design of preventative and therapeutic agents that combat the disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Macromolecular Structure and Function B Study Section (MSFB)
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Wehrle, Janna P
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University of Alaska Anchorage
Schools of Arts and Sciences
United States
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Vugmeyster, Liliya; Griffin, Aaron; Ostrovsky, Dmitry et al. (2018) Correlated motions of C'-N and C?-C? pairs in protonated and per-deuterated GB3. J Biomol NMR 72:39-54
Vugmeyster, Liliya; Ostrovsky, Dmitry (2018) Basic experiments in 2H static NMR for the characterization of protein side-chain dynamics. Methods 148:136-145
Vugmeyster, Liliya; Ostrovsky, Dmitry; Hoatson, Gina L et al. (2017) Solvent-Driven Dynamical Crossover in the Phenylalanine Side-Chain from the Hydrophobic Core of Amyloid Fibrils Detected by 2H NMR Relaxation. J Phys Chem B 121:7267-7275
Vugmeyster, Liliya; Ostrovsky, Dmitry (2017) Comparative Dynamics of Methionine Side-Chain in FMOC-Methionine and in Amyloid Fibrils. Chem Phys Lett 673:108-112
Vugmeyster, Liliya; Ostrovsky, Dmitry (2017) Static solid-state 2H NMR methods in studies of protein side-chain dynamics. Prog Nucl Magn Reson Spectrosc 101:1-17
Vugmeyster, Liliya; Ostrovsky, Dmitry; Clark, Matthew A et al. (2016) Fast Motions of Key Methyl Groups in Amyloid-? Fibrils. Biophys J 111:2135-2148
Vugmeyster, Liliya; Clark, Matthew A; Falconer, Isaac B et al. (2016) Flexibility and Solvation of Amyloid-? Hydrophobic Core. J Biol Chem 291:18484-95
Vugmeyster, Liliya; Ostrovsky, Dmitry; Villafranca, Toni et al. (2015) Dynamics of Hydrophobic Core Phenylalanine Residues Probed by Solid-State Deuteron NMR. J Phys Chem B 119:14892-904