Thesis

Time-resolved emission spectra of intrinsic Tyrosine during the early stages of ß-amyloid aggregation

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2022
Thesis identifier
  • T16258
Person Identifier (Local)
  • 201682054
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The aggregation of beta-amyloids (Aß) is one of the key processes responsible for the development of Alzheimer's disease (AD). Early molecular-level detection of beta-amyloid oligomers may help in early diagnosis and in the development of new intervention therapies. Previous studies on the changes in beta-amyloid's single tyrosine intrinsic fluorescence response during aggregation can be efficiently used to indicate the extent of the aggregation at its earliest stages before the beta-sheets are formed. To better understand the underlying kinetics of Aß aggregation we present a complementary approach based on the time-resolved emission spectra (TRES) of amyloid's tyrosine. TRES can sufficiently demonstrate structural changes on the nanosecond time scale after excitation. Aß monomers can be distinguished from oligomers by means of the position of their emission spectra. Further spectral shift caused by dielectric relaxation can be useful for determining the size of the oligomers since their spectral shift gradually decreases as the aggregates grow larger. Aß1-40 self-assembly was also studied in the presence of additional compounds affecting the progress of aggregation such as copper ions and glucose or factors that can potentially prevent aggregation like quercetin. In the presence of copper ions, time‐resolved fluorescence techniques demonstrated the formation of beta amyloid‐copper complexes and the accelerated peptide aggregation. The shifts in the emission spectral peaks indicated that the peptides exhibit different aggregation pathways than in the absence of copper. In the presence of high glucose concentrations TRES exhibit multiple peaks, their position and shifts reveal the impact of glycation on Aβ1– 40 oligomerisation. The results show that formation of the advanced glycation end products (AGEs) alters the aggregation pathway. These changes are highly relevant to our understanding of the pathophysiology of AD and the implication of AGE and diabetes in these pathways. In the presence of quercetin, TRES exhibit multiple peaks with characteristic spectral shifts, indicating a different aggregation pathway. At a molar ratio of 1:1 (Aß1-40 : Quercetin), TRES results showed early formation of Aß-Quercetin complexes, which seem to inhibit further Aß aggregation. This makes it a potential nutrient that may help prevent or delay the development of Alzheimer’s disease. Other techniques like fluorescence anisotropy decay and nanoparticle tracking analysis (NTA) were investigated in order to study Aβ aggregation and to explore synergy resulting from combining different experimental techniques.
Advisor / supervisor
  • Rolinski, Olaf
  • Birch, David
Resource Type
Note
  • Error on title page. Date of award is 2022.
DOI

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