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THE ROLE OF TRANSLATION ELONGATION DEFICITS IN ALZHEIMER’S DISEASE PATHOGENESIS

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title
THE ROLE OF TRANSLATION ELONGATION DEFICITS IN ALZHEIMER’S DISEASE PATHOGENESIS
author
Beckelman, Brenna Claire
abstract
Alzheimer’s disease (AD), the most common form of dementia in the elderly, is poised to become a global threat to public health. With a dearth of disease-modifying treatments, it is crucial that we identify novel therapeutic targets based on mechanistic studies of the underlying molecular pathways contributing to AD-associated memory loss. Synaptic dysfunction is a key early event in AD pathophysiology. Both synaptic function and memory formation require de novo protein synthesis (i.e. mRNA translation). Studies examining brain specimens from human patients and transgenic AD animal models show impairments in protein synthesis and the translational machinery. Much of this work has focused on the role of initiation, the first phase of translation, in AD-associated memory and synaptic plasticity deficits. By comparison, far fewer studies have examined the peptide chain elongation phase in AD. Here, we provide evidence for elongation dysregulation in AD. We examined the two primary facilitators of elongation, eukaryotic elongation factor 1A (eEF1A) and eukaryotic elongation factor 2 (eEF2). Hippocampal eEF1A expression was diminished in human AD patients and transgenic AD model mice. Furthermore, treatment with amyloid beta (Aβ) significantly reduced eEF1A expression in acute hippocampal slices. Using mice lacking the gene for tuberous sclerosis complex 2 (TSC2+/-), an upstream negative regulator of eEF1A, we upregulated eEF1A expression and prevented Aβ-induced synaptic plasticity deficits. Unlike eEF1A, expression of eEF2 was not altered in hippocampal samples from human AD patients. Instead, eEF2 exhibited hyperphosphorylation in the AD hippocampus. This phosphorylation was recapitulated in AD model mice. Phosphorylation of eEF2 at 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 phosphorylation. To determine whether repression of eEF2K activity (and thus eEF2 phosphorylation) would impact AD-associated deficits, we crossed heterozygous eEF2K knock down mice with AD model mice. Genetic reduction of eEF2K alleviated hippocampal eEF2 hyperphosphorylation and restored de novo protein synthesis capacity in AD model animals. Moreover, eEF2K knock down rescued AD-affiliated impairments in hippocampal-dependent memory formation and synaptic plasticity. AD mice with genetically reduced levels of eEF2K showed enhanced dendritic spine density and maturation, more postsynaptic densities (PSDs), and alterations in the expression of key synaptic plasticity-related proteins. In summary, we show that translation elongation dysregulation contributes to AD pathophysiology, and correcting elongation deficiencies can alleviate deficits in memory formation and synaptic function in AD. Our work suggests that targeting elongation, specifically eEF1A and eEF2/eEF2K, could serve as a potential therapeutic target for AD treatment.
subject
Alzheimer's disease
elongation
learning and memory
protein synthesis
synaptic plasticity
translation
contributor
Ma, Tao (committee chair)
Craft, Suzanne (committee member)
Furdui, Cristina (committee member)
Raab-Graham, Kimberly (committee member)
date
2018-05-24T08:35:45Z (accessioned)
2019-05-23T08:30:13Z (available)
2018 (issued)
degree
Neuroscience (discipline)
embargo
2019-05-23 (terms)
identifier
http://hdl.handle.net/10339/90683 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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