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Approaches In Fast-Scan Cyclic Voltammetry (fscv) For Millisecond-Scale Detection Of Cu(ii) And Ros Dynamics
Nudurupati, Uma
Nudurupati, Uma
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Neurodegenerative disorders, such as Alzheimer's disease (AD), are characterized by plaques rich in amyloid beta (Aβ) peptides. These amyloid plaques comprise of Aβ peptide both in aggregate and fibril form. The fibril form can further display structural diversity, forming distinct polymorphs despite identical amino acid sequences. Clinical evidence from patients suffering from neurodegeneration demonstrates that individuals with different clinical histories harbor unique fibril conformations, with twisted structures typically exhibiting greater neurotoxicity than ribbon-like arrangements. Notably, neural and vascular deposits within the same patient can exhibit distinct structural characteristics, indicating tissue-specific pathological processes.Apart from the peptides, the plaques found in both AD and Cerebral Amyloid Angiopathy(CAA) have been known to contain Cu(II) in high concentration. The role of copper ions in the AD pathological cascade has been controversial, with some research suggesting Cu(II) may protect against excitotoxicity by modulating N-methyl D-aspartate receptor activity, while competing evidence indicates the neurotoxicity of Cu(II). For instance, Cu(II) promotes Aβ aggregation and independently generates reactive oxygen species (ROS), both of which contribute to cellular damage and reinforce a self-perpetuating cycle of oxidative stress and protein aggregation. Traditional analytical techniques lack the temporal resolution necessary to capture the rapid dynamics of these molecular interactions, particularly the transient presence of free Cu(II) and ROS species like H2O2. This dissertation aims to develop tools and employ fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes (CFMs) to achieve millisecond-scale monitoring of these processes. By creating a simplified Cu(II)-selective sensor through direct anodic deposition of 1,4-diethynylbenzene, we aim to provide a tool to the community for evaluating the temporal relationships between Cu(II) fluctuations and ROS generation. Moreover, by monitoring ROS released from model neuronal cells in response to Aβ structural variants, we aim to assess whether certain Aβ fibril polymorphs induce greater hydrogen peroxide (H₂O₂) release, both in frequency and concentration. By establishing these structure-function relationships and providing a new tool, this research aims to provide crucial insights into the molecular basis of AD and CAA, contributing to potentially identifying novel therapeutic targets for intervention.
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2026
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