| dc.identifier.uri | http://hdl.handle.net/11401/76490 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Familial mutations in the amyloid precursor protein (APP) are known to influence how the protein is processed to form the Aβ peptides associated with Alzheimer's disease (AD). The Aβ peptides range from ~38-42 residues in length. The A&beta40; peptide is the most abundant cleavage product of APP. However, the A&beta42; peptide predominates in brain plaques, the pathological hallmark of AD. In this thesis, I address the influence of mutations located within the extracellular domain in the processing of APP to Aβ 40 and A&beta42; . I also describe studies on the interaction of Aβ 42 with model membrane bilayers and the fragments of the human prion protein. The β C-terminal fragment (&beta-CTF) is the product of APP cleavage by the β - and γ -secretases. The extracellular sequence of the β -CTF contains three residues (AED) that are sites of early onset familial AD mutations as well as a hydrophobic stretch of residues (LVFF) that is inhibitory and influences fibril formation of Aβ . Our measurements of a series of N terminal mutations utilizing Fourier transform infrared (FTIR) spectroscopy showed that the extracellular sequence plays a role in regulating the processing of APP by forming a defined structural domain. The α -CTF is the product of APP cleavage by the α - and γ -secretases. However, the α -CTF is a much poorer substrate for γ -secretase. This observation implies that the first 16 amino acids of the β -CTF are critical in regulating its cleavage by γ -secretase. In my research work, I further found that the transmembrane domain forms much stronger dimers in the context of peptides mimicking the α -CTF than the β -CTF. Such discoveries lead to the hypothesis that both dimerization and the extracellular sequence of the β -CTF play roles in regulating γ -secretase processing. After APP is sequentially cleaved by the β and γ secretases, toxic Aβ 42 is released to the extracellular milieu. Previous studies showed that the oligomer form of Aβ 42 is more toxic than its fibril form. However, the mechanism of toxicity is poorly understood. In this study, by employing a suite of biophysical methods, the secondary structural variation of Aβ 42 upon interaction with model membrane bilayers and with the human prion protein has been addressed, which greatly facilitates the interpretation of the toxicity mechanism of Aβ 42. | |
| dcterms.available | 2017-09-20T16:50:24Z | |
| dcterms.contributor | Smith, Steven O | en_US |
| dcterms.contributor | London, Erwin | en_US |
| dcterms.contributor | Brown, Deborah | en_US |
| dcterms.contributor | Van Nostrand, William | en_US |
| dcterms.contributor | Constantinescu, Stefan. | en_US |
| dcterms.creator | Hu, Yi | |
| dcterms.dateAccepted | 2017-09-20T16:50:24Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:24Z | |
| dcterms.description | Department of Molecular and Cellular Biology. | en_US |
| dcterms.extent | 135 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/76490 | |
| dcterms.issued | 2013-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:24Z (GMT). No. of bitstreams: 0
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Aβ , Amyloid precursor protein, FAD, FTIR, NMR, prion | |
| dcterms.subject | Biophysics | |
| dcterms.title | Structural Insights into the Processing of the Amyloid Precursor Protein and Aβ 42 Toxicity | |
| dcterms.type | Dissertation | |
