Development of Chemical Tactics to Study Fundamental Aspects of Pathogenic Factors Found in Neurodegenerative Diseases

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Development of Chemical Tactics to Study Fundamental Aspects of Pathogenic Factors Found in Neurodegenerative Diseases
Kang, Juhye
Kwon, Tae-Hyuk
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Graduate School of UNIST
Amyloidogenic peptides are considered central pathological factors in neurodegenerative diseases; however, their roles in the pathologies of the diseases have not been fully understood. Amyloidogenic peptides have indicated their multiple faces on formation, aggregation, and accumulation that portray the complexity of the intrinsically disordered protein stemming from their convoluted structure and heterogeneous nature. Although the latest research suggests oligomeric forms of amyloidogenic peptides as toxic species towards neurodegeneration, their direct involvements in the pathologies and the corresponding mechanistic details remain rudimentary. Therefore, novel chemical approaches to modify amyloidogenic peptides at the molecular level would be useful in advancing our comprehension of those aspects and the subject. In Chapter 1, we briefly introduce outline and discuss possible therapeutic targets in Alzheimer’s disease. In Chapter 2, the design of an Ir(III) complex, Ir-1, is described as a chemical tool for oxidizing amyloidogenic peptides upon photoactivation and subsequently modulating their aggregation pathways. Biochemical and biophysical investigations illuminate that the oxidation of representative amyloidogenic peptides [i.e., amyloid-beta (Abeta), alpha-synuclein, and human islet amyloid polypeptide] is promoted by light-activated Ir-1, which can alter the conformations and aggregation pathways of the peptides. In Chapter 3, effective chemical strategies for modifications of Abeta peptides implemented by a single Ir(III) complex are illustrated. Such peptide variations can be achieved by our rationally designed Ir(III) complexes leading to the significant modulation of the aggregation pathways of Abeta40 and Abeta42 as well as the production of toxic Abeta species. Amyloidogenic peptides can coordinate to metal ions, including Zn(II), which can subsequently affect the peptides' aggregation and toxicity, leading to neurodegeneration. Unfortunately, the detection of metal–amyloidogenic peptide complexation has been very challenging. In Chapter 4, we report the development and utilization of a probe (A-1) capable of monitoring metal–Abeta complexation based on Förster resonance energy transfer (FRET). Moreover, as the FRET signal of Zn(II)-added A-1 is drastically changed when the interaction between Zn(II) and A-1 is disrupted, the Zn(II)-treated probe can be used for screening a chemical library to determine effective inhibitors against metal–Abeta interaction. Overall, we demonstrate chemical tactics for modifications of amyloidogenic peptides in an effective and manageable manner utilizing the coordination capacities and/or photophysical properties of chemical reagents. Our approaches will provide the foundation for developing effective and efficient methods for elucidating fundamental properties of pathological factors at the molecular level and assisting in identifying therapeutic candidates against neurodegenerative disorders.
Department of Chemistry
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