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Thesis
Investigating Tip60 HAT-specific activators as a potential epigenetic-based therapeutic for Alzheimer's disease
Master of Science (M.S.), Drexel University
Jun 2024
DOI:
https://doi.org/10.17918/00010652
Abstract
Alzheimer's Disease (AD) is a progressive and irreversible neurological disorder that primarily affects cognitive functions, particularly learning, memory, and reasoning. Lifestyle factors with the complex combination of genetics, age, and environment can lead to the risk of developing AD and can influence the epigenetic programming mediated neural gene control. Histone acetylation reduction in the AD brain is a widespread hallmark linked to neural gene repression and cognitive decline. Current treatments in the field of pharmacotherapeutics aim to restore the histone acetylation imbalance by the inhibition of histone deacetylases (HDACs), which shows promising results in improving cognition but often face complications in clinical translation due to their non-specific widespread hyperacetylation issues. Exploring the full potential of enhancing the activity of neuroprotective histone acetyltransferases like Tip60, which play a unique role in countering AD pathology, presents a new route for therapeutic investigation. Our lab has previously shown that in both human AD hippocampus and fruit fly AD model brains, there's a decrease in both mRNA and protein Tip60 HAT levels and an abnormal increase in HDAC2 protein levels which leads to dysregulation in histone acetylation homeostasis, resulting in the suppression of synaptic plasticity genes and cognitive impairment. Notably, increasing Tip60 levels genetically in fruit fly AD brains prevents all these deficits. Due to these findings, we hypothesized that enhancing Tip60's HAT activity pharmacologically will mimic its neuroprotective function in AD. Using lab-generated Tip60 HAT-specific activators, we were able to observe the effective restoration of locomotor deficits and early lethality in the fruit fly AD model, highlighting the compounds' therapeutic potential.
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Details
- Title
- Investigating Tip60 HAT-specific activators as a potential epigenetic-based therapeutic for Alzheimer's disease
- Creators
- Gu Gu Nge
- Contributors
- Ryan J. Petrie (Advisor)Felice Elefant (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 52 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 991021890114504721