Doctor of Philosophy (PhD)
Neuronal cytotoxicity observed in Alzheimer¡¦s disease (AD) is linked to the aggregation of £]-amyloid peptide (A£]) into toxic forms. Increasing evidence points to oligomeric species as the neurotoxic species compared to fibrils; disruption or inhibition of A£]ƒnself-assembly into oligomeric or fibrillar forms remains a viable therapeutic strategy to reduce A£] neurotoxicity. Amyloid aggregation mitigating peptides (AAMPs) were designed based on the A£]ƒn¡§hydrophobic core¡¨ A£]17-20, with C£\,£\-disubstituted amino acidsƒnƒv£\£\AAs) added into this core as disrupting agents. The number, distribution, and side chain functionality of £\£\AAs incorporated into the mitigator sequence was found influences the resultant aggregate morphology as indicated by ex-situ experiments using AFM and TEM. For instance, AAMP-5 incorporating the sterically hindered diisobutyl side chain to its core sequence disrupted fibril formation. However, AAMP-6 with a dipropyl side chain incorporated into its core sequence only altered fibril morphology, forming shorter and larger sized fibrils compared to those of A£]1-40. Interestingly, £\£\AA-AAMPs also disassembled preformed fibrils to produce either amorphous aggregates or protofibrillar structures, suggesting the existance of an equillibrium between fibrils and prefibrillar structures. Also, AAMPs aged alone did slowly aggregate to form spherical structures, which is inconsistent with circular dichroism spectra showing an unchanged random coil structure. Several potent mitigators of A£] fibrillization were derived from N- or C- terminus modification of KLVFF with various polar groups. The number of £\£\AAs and polar groups were reduced without affecting the overall disruptive properties of the mitigator.
Document Availability at the Time of Submission
Secure the entire work for patent and/or proprietary purposes for a period of one year. Student has submitted appropriate documentation which states: During this period the copyright owner also agrees not to exercise her/his ownership rights, including public use in works, without prior authorization from LSU. At the end of the one year period, either we or LSU may request an automatic extension for one additional year. At the end of the one year secure period (or its extension, if such is requested), the work will be released for access worldwide.
Bett, Cyrus Kipkurui, "Amyloid Aggregation-Mitigating Peptides As Potential Alzheimer's Drugs" (2009). LSU Doctoral Dissertations. 1865.
Hammer, Robert P.