Advisor(s)
David Knight
Andrew Pickering
Committee Member(s)
Andrew Pickering
Christanne Strang
David Knight
Farah Lubin
Mariangela Scarduzio
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Psychology
Date of Award
9-11-2025
Abstract
Proteostasis is essential for the degradation of oxidized, misfolded proteins and proper function of neuronal plasticity. Proteasome inhibition has been shown to exacerbate cognitive and behavioral deficits in aging and Alzheimer’s Disease (AD) models. Proteasomal activity is decreased across human and animal models of AD. We hypothesize that aging and AD markers, β-amyloid and/or hyperphosphorylated tau, impair proteasome function, thereby preventing the proteasome’s capacity to degrade critical synaptic proteins essential for memory formation. We investigated the role of pharmacological and genetic augmentation on proteasomal function, to rescue aging and AD-like cognitive deficits in cell culture, Drosophila, and mice. We demonstrate that β-amyloid disrupts 20S proteasome function while simultaneously driving the disassembly of 26S proteasome into free 20S proteasome. Treatment with proteasome activators enhances the 20S and 26S proteasome function and reduces cell death caused by Aβ42 toxicity in SK-N-SH cells. In our AD Drosophila models, our proteasome agonists delayed mortality and restored cognitive function. Chronic treatment with proteasome activators protected against deficits in working memory caused by Aβ42 infusion in mice. In a genetic mouse model of AD, hAPP(J20) with established cognitive deficits, acute drug treatment significantly improved spatial learning deficits, with treated mice performing comparably to control models, our proteasome agonist delayed mortality and restored cognitive function. Our proteasome agonist shows promise in mitigating aging and AD-like cognitive deficits by enhancing proteasome function and assembly. These findings suggest that targeting proteasome activity could be a viable therapeutic approach for cognitive decline in neurodegenerative diseases and aging, warranting further investigation into the mechanistic properties of proteasome modulation on synaptic plasticity.
ProQuest ID
Recommended Citation
Davidson, Kanisa, "Proteasome Augmentation Is Protective Against Alzheimer’S Disease And Agerelated Cognitive Decline" (2025). All ETDs from UAB. 7407.
https://digitalcommons.library.uab.edu/etd-collection/7407
