Masters Theses
Date of Award
5-2003
Degree Type
Thesis
Degree Name
Master of Science
Major
Life Sciences
Major Professor
Ronald Wetzel
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extensive deposition of amyloid plaques in the brain. These plaques contain an amyloid fibril core that is formed through self-aggregation of the P-amyloid peptide (AP), a proteolytic product of amyloid precursor protein (APP). AP aggregation is currently thought to play a causative role in the development of AD, and thus is an attractive target for potential therapeutics. A library of pharmaceutically active compounds (LOP AC) was screened for potential inhibitors of AP aggregation using a 96 -well microplate assay. No inhibitors were found in the library, but, surprisingly, several compounds exhibited a stimulatory effect on AP deposition. Two of the most potent stimulatory compounds from the library (NPC 15437 and calmidazolium chloride) were chosen for more detailed studies, with the hope that they might offer some insight into mechanistic and structural aspects of AP aggregation, as well as providing possible ideas for drug development. NPC 15437 was found to stimulate the nucleation phase of AP aggregation in a concentration dependent manner through an interaction with monomeric AP peptide. Calmidazolium chloride at a concentration of 100 µM was observed to stimulate the formation of an aggregated state of AP that is clearly distinct from mature amyloid fibrils. Based on these findings the compounds described here (a) could possibly offer insight into the mechanism by which amyloid is formed, as well as the chemical structures that are important to amyloid formation, (b) could be used to test the amyloid hypothesis in mouse models of AD, and (c) may be of some importance in the development of AD therapeutics
Recommended Citation
Sega, Matthew, "Stimulators of Aβ aggregation identified through drug screening. " Master's Thesis, University of Tennessee, 2003.
https://trace.tennessee.edu/utk_gradthes/5292