Year: 2011
Type: dissertation
Abstract: Self-assembling peptides, such as amyloid beta and heat shock protein 27 (Hsp27), contribute to pathologies and essential cell functions.Progressive aggregation of amyloid beta (Aβ) peptide is responsible for the pathologies of Alzheimer's disease (AD).Recent evidence suggests that Aβ aggregates are found in a variety of conformations, including globular oligomers and linear fibrils, which oligomers are found to be more neurotoxic than other Aβ conformations.Meanwhile, Hsp27 functions as a chaperone in oligomeric structure but works as an apoptotic regulator in its monomeric state.Hsp27 is neuroprotectant and has been shown to diminish neuronal aggregates.Hence, substances that interact selectively with different Aβ conformations and that promote Hsp27 oligomeric formation would be useful tools in developing chemical probes to study the molecular recognition structures that are essential in Aβ peptide and Hsp27 self-assembly and in developing potential therapeutics for AD.To identify substances that selectively impact different Aβ conformations, we screened 24 known Aβ ligands and WKLVFF peptide against Aβ oligomers and fibrils at different time points using fluorescence assays.We discovered that three tetracyclines specifically inhibit fibril aggregation at all time points, but complete inhibition of oligomer formation only occurs when compounds were added prior to aggregation.The fluorescence of WKLVFF peptide was also selectively quenched (55.44±4.08%) in the presence of fibrils, but slight increased (8.40±3.13%) in oligomers.These results suggest that tetracyclines and WKLVFF may bind to a hydrophobic domain that is critical in Aβ aggregation and this domain is exposed distinctively in fibril and in mature oligomers.In a parallel study, we aimed to identify small molecule modulators of Hsp27 activity by screening 35 compounds using turbidity assay.We observed that several hydrophobic or aromatic compounds effectively induce Hsp27 oligomerization.This result proposes that these sterols interact with the conserved hydrophobic motif on Hsp27 and modulate its surface hydrophobicity.The understanding of structures that are essential in Aβ peptide and Hsp27 self-assembly permits further rational design of small molecules or biologics that could selectively probe for specific conformations of Aβ and manipulate the aggregation of Aβ peptide and Hsp27.
Author: Han Yiau Seh
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W191932423