A two dimensional biomimetic approach to the amyloidogenesis
Date of Award
Doctor of Philosophy (Ph.D.)
First Committee Member
Roger M. Leblanc - Committee Chair
This dissertation describes a novel two-dimensional (2D) strategy to study amyloid beta peptide (Abeta). Alzheimer's disease (AD) is a disorder that destroys cells in the brain. AD is linked to the amyloid plaques which consist of dense aggregation of peptides, called amyloid beta or Abeta. These polypeptides are found between nerve cells (neurons) in the brain. It is well known that insoluble polypeptide and protein monolayers at the air-liquid interface are very applicable as biomimetic models for studying aggregation, conformation, and molecular orientation; this approach has the advantage of simulating the phenomenon in vivo without using organic solvents, then a 2D approach could be applied to investigate the cause of Abeta aggregation.The purpose of this work will be aimed at explaining the aggregation mechanism. However, the insolubility of Abeta makes it difficult to study the fibrils behavior from AD brain. Our objective was to investigate the aggregation of small fragments of the Abeta(1-42), which is present in AD, namely Abeta(31-35) and Abeta(25-35). These fragments present the same structural characteristic of Abeta and preserve its neurotoxicity. By choosing synthetic peptides homologous to the full length Abeta, we may expect fibril-like aggregates formation in vitro. Surface chemistry was used to examine the aggregation process, whereas epi-fluorescence microscopy was utilized to observe the topography of the domains. Circular Dichroism (CD), ATR-FTIR and PM-IRRAS spectroscopies were used to study the conformation of the domains in different environments. Fibril-like aggregates were formed using our approach and they were characterized with the above mentioned techniques.Finally, full length Abeta and its fragments were labeled using luminescent CdSe/ZnS Quantum Dots (QDs) and conventional fluorophores, as well. The use of QDs rendered a better contrast and a higher intensity for all the imaging. If we are able to understand the aggregation mechanism, the possibility of slowing or even preventing the disease will seem a feasible task.
Chemistry, Physical; Health Sciences, Pathology
Naistat, David, "A two dimensional biomimetic approach to the amyloidogenesis" (2006). Dissertations from ProQuest. 2428.