PhD Dissertation Defense by Sarah Auguste McCaulley "Targeting Copper-Mediated Aβ Neurotoxicity, Tau Phosphorylation and Oxidative Stress in Alzheimer’s Disease Using Cranberry-Derived Polyphenols"
Abstract:
Copper has been linked to the pathogenesis of Alzheimer’s Disease (AD) as it binds to amyloid beta (Aβ) and tau, impacting their aggregation and generating reactive oxygen species (ROS). Metal chelation therapy has emerged as a potential treatment strategy for amyloid diseases like AD. Flavonoids including polyphenols in cranberries chelate metals and have shown neuroprotective effects in AD, however, their mechanisms of action remain poorly understood. This study will investigate the effects of cranberry extracts, subfractions and polyphenols—including quercetin and its metabolites isorhamnetin and tamarixetin—on copper-mediated Aβ/tau-induced oxidative stress, Aβ neurotoxicity, and tau phosphorylation with the following specific aims: 1) Assess cranberry's ability to attenuate copper mediated Aβ/tau induced ROS; 2) Investigate the impact of cranberries/copper on the formation of α-sheet structure in Aβ/tau; 3) Evaluate the impact of cranberries/copper on the formation of Aβ oligomers; 4) Evaluate the impact of cranberries on copper induced tau phosphorylation. Cranberry’s impact on SH-SY5Y neuroblastoma cell viability will be assessed using an MTT assay prior to evaluating its ability to reduce copper-mediated Aβ and tau-induced ROS by confocal microscopy. The effects on α-sheet structure in Aβ and tau will be examined via CD and FTIR spectroscopy. Aβ oligomers will be analyzed by developing a Homebrew Custom Simoa assay with an α-sheet peptide or a monoclonal antibody and by developing a confocal microscopy method using a fluorescent α-sheet peptide. Cranberry’s effects on copper-induced tau phosphorylation will be evaluated using commercially available Simoa® and Atellica® IM immunoassays. These studies will contribute to a better understanding of the mechanisms of action of copper's role in AD and cranberry polyphenols’ neuroprotective effects, providing valuable insight for the development of therapeutics targeting metal-chelation oxidative stress, Aβ neurotoxicity, and tau phosphorylation in AD.
Dissertation advisor: Dr. Maolin Guo
Dissertation Committee members:
Dr. Catherine Neto (Chemistry);
Dr. Shuowei Cai (Chemistry);
Dr. Isabelle Phillip (Siemens Healthineers)
Zoom Meeting
: https://umassd.zoom.us/j/96549246129?pwd=Zp8S78A354o695z9agxvS0febTLr9E.1 Meeting ID: 965 4924 6129 Passcode: 082135
Heather Blaser/Rachel White
508-999-8232
hblaser@umassd.edu
https://umassd.zoom.us/j/96549246129?pwd=Zp8S78A354o695z9agxvS0febTLr9E.1