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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM111681-01
Application #
8758768
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
2014-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$344,736
Indirect Cost
$116,736
Name
University of Alaska Anchorage
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
076664986
City
Anchorage
State
AK
Country
United States
Zip Code
99514