Advisory Committee Chair
Andrew M Pickering
Advisory Committee Members
Andrew E Arrant
Goldberg S Matthew
Document Type
Thesis
Date of Award
2023
Degree Name by School
Master of Science (MS) Heersink School of Medicine
Abstract
The proteasome is a large multi-subunit protease responsible for the degradation and removal of oxidized, misfolded, and polyubiquitinated proteins. The proteasome plays a critical role in nervous system processes. This includes the maintenance of cellular homeostasis in neurons (1). It also includes synaptic efficacy and plasticity as well as protein turnover, presynaptic vesicle transport, and neuronal protesostasis. Proteasome function is impaired as a consequence of aging, which is aggravated by conditions like Alzheimer's Disease and Related-Dementias (AD, ADRD) (2). According to earlier work from our lab the proteasome is critical to how quickly AD progresses. In Drosophila, human cells, and model of Alzheimer’s disease, proteasome depletion has been shown to accelerate AD-like pathology and cognitive deficits, whereas proteasome augmentation has been shown to attenuate these features (2). We also demonstrated that proteasome activators enhanced turnover of the amyloid precursor protein and prevention of overall proteostatic dysfunction and the protective effects of proteasome overexpression, at least iv in part, from increased degradation of APP, resulting in reduced Aβ. However, it is not clear if the protective effects are fully dependent on the ability of proteasome to turnover amyloid precursor proteins. In this study we investigate if proteasome augmentation may protect against AD progression independent of modulation of Aβ machinery. Here we used Elav-Gs-GAL4>UAS-Aβ42 flies, which overexpress pre-formed Aβ1-42 we demonstrate using treatment with proteosome activators (TAT1-8,9TOD, TAT1-DEN). That proteasome augmentation can protect against cognitive and survival deficits from Aβ42 but not in motor deficits.
Recommended Citation
Bano, Mehar, "Pharmacologic Proteasome Activators Ameliorate Alzheimer's-Like Pathology in Ad Fly Models" (2023). All ETDs from UAB. 465.
https://digitalcommons.library.uab.edu/etd-collection/465