Amyloid fibrils results from a type of ordered polypeptide aggregation that is associated
with ailments such as Alzheimer's disease (AD). Annually, millions of people in the
United States alone develop and die from AD. Therefore, it is necessary to understand
not only the process of amyloid formation, but also the causes of this specific type of
aggregation. This study used ABeta(25-35) since it is a fragment of the Alzheimer?s
peptide that behaves like the full length peptide found in patients with AD.
To study the process of amyloid formation, several methods were used so that a more
complete picture of the stepped aggregation process could be realized. Several
oligomeric species were detected and described many of which could not have been
observed without using the complete battery of methods utilized here. The oligomeric
species detected included a novel 'rolled sheet' that appeared to be the immediate
precursor of amyloid fibrils, and two supermolecular species that appear after amyloid
fibrils were formed. In determining the causes of amyloid formation, two significant discoveries were made.
First, by partial sequence randomization, truncation, and Ala scanning mutagenesis, the
critical amyloidogenic region of ABeta(25-35) was found to be residues 30-35. This critical
core region is important because it is thought to be the region that initiates amyloid
formation, therefore knowing the residues involved in the region is a useful tool for
developing methods of fibril formation prevention. Second, by inserting all naturally
occurring amino acids into position 34 of ABeta(25-35), three distinct classes of variants
were observed and the effect of several physiochemical properties on amyloidosis were
examined. Hydrophobicity, solubility, and ?-strand propensity were found to affect
aggregation to the greatest extent. Also within these two studies, our results suggest that
early oligomers are the cytotoxic species as opposed to amyloid fibrils or other larger
macromolecular assemblies.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/ETD-TAMU-2009-12-7339 |
| Date | 2009 December 1900 |
| Creators | Ridinger, Katherine V. |
| Contributors | Scholtz, John M. |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | application/pdf |
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