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THERAPEUTIC POTENTIAL OF EUKARYOTIC ELONGATION FACTOR 2 KINASE INHIBITORS FOR ALZHEIMER'S DISEASE

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abstract
The prevalence of Alzheimer’s disease (AD) is expected to increase rapidly over the coming decades due to a growing aging population. Currently, there are no disease-modifying treatments for AD, and the basic underlying mechanism of the disease is still unknown. Therefore, it is crucial that we identify novel therapeutic targets based on mechanistic studies of the underlying molecular pathways of AD. Cognitive deficits, specifically learning and memory impairments, are a key pathology of the disease, and are the result of synaptic dysfunction. Long-term forms of synaptic plasticity and memory formation require de novo protein synthesis (i.e. mRNA translation). Post mortem human brain samples and transgenic AD animal models show impairments in protein synthesis and associated translational machinery. Until recently, the majority of this work had focused on the role of initiation, the first phase of translation, in AD-associated memory and synaptic plasticity deficits. Recent evidence suggests an important role for elongation dysregulation in AD. Previous work from our lab has shown AD-associated dysregulation of a primary facilitator of elongation, eukaryotic elongation factor 2 (eEF2). Hippocampal tissue from AD patients showed a hyper-phosphorylation of eEF2, which was also observed in transgenic AD model mice. Phosphorylation of eEF2 (Thr 56) inhibits its function and suppresses general protein synthesis. Eukaryotic elongation factor 2 kinase (eEF2K) is the only known kinase to perform this specific inhibitory phosphorylation. To determine whether suppression of eEF2K activity would impact AD-associated deficits, homozygous eEF2K knockout mice were crossed with APP/PS1 (APP) AD model mice. I found that genetic knockout of eEF2K alleviated hippocampal eEF2 hyper-phosphorylation and restored cognitive deficits in APP mice.
subject
Aging
Alzheimer's Disease
Animal Models
Dementia
Novel Therapeutics
Protein Synthesis
contributor
Kasica, Nicole Patricia (author)
Ma, Tao (committee chair)
Macauley, Shannon (committee member)
Craft, Suzanne (committee member)
Furdui, Cristina (committee member)
date
2022-01-15T09:35:30Z (accessioned)
2022 (issued)
degree
Neuroscience (discipline)
2022-07-14 (liftdate)
embargo
2022-07-14 (terms)
identifier
http://hdl.handle.net/10339/99386 (uri)
language
en (iso)
publisher
Wake Forest University
title
THERAPEUTIC POTENTIAL OF EUKARYOTIC ELONGATION FACTOR 2 KINASE INHIBITORS FOR ALZHEIMER'S DISEASE
type
Dissertation

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