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The Roles of AMP-Activated Protein Kinase α Isoforms in Alzheimer’s Disease

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abstract
Currently, there exists no viable treatment, cure, or preventative intervention for Alzheimer’s disease (AD), a progressive neurodegenerative disease leading to memory loss in the elderly. As the disease progresses, neurons lose their regulation of signaling pathways and energy homeostasis - both of which are critical for maintaining brain health and function. Finding and understanding the molecular pathways that underlie synaptic plasticity regulation in physiological and pathological states is critical for developing new targets for AD. AMP-activated protein kinase (AMPK) acts as a central cellular energy sensor to maintain cellular energy homeostasis. Furthermore, AMPK integrates several signaling pathways (including eukaryotic elongation factor 2 (eEF2)) controlling de novo protein synthesis. Mammalian AMPK is a heterotrimeric protein with a catalytic α subunit and regulatory β/γ subunits. The α subunit of AMPK exists in two isoforms: α1 and α2, and their roles in AD are unknown. By investigating brain tissue from post-mortem human AD patients and a transgenic mouse model of AD, we have found that levels of AMPKα1 are dramatically increased while levels of AMPKα2 are decreased. This project utilized novel transgenic mouse lines in which PRKAA1 and PRKAA2 (genes that encode AMPK α1 and α2 subunits, respectively) were removed in excitatory neurons in the forebrain and the hippocampus late in development, to generate brain- and isoform-specific conditional AMPKα1 and α2 knockout mice (α1 cKO and α2 cKO). We have further crossed the heterozygous AMPKα1/2 cKO mice with the Tg19959 AD mouse model to generate Tg19959/AMPKα1(+/-) and Tg19959/AMPKα2(+/-) double mutant mice. Suppression of AMPKα1 but not α2 was sufficient to alleviate AD-associated cognitive impairments, independently of amyloid-beta pathology. α1 but not α2 reduction also restored AD-associated impairments in dendritic spine density and maturity, post-synaptic density formation, mitochondrial morphology, and de novo protein synthesis. Lastly, AMPKα1 but not α2 reduction alleviated AD-associated eEF2 hyperphosphorylation. Our results reveal AMPK isoform homeostasis disruption in AD and a novel role of the AMPK isoforms in AD-assoicated pathophysiology in vivo.
subject
Alzheimer's Disease
AMPK
eEF2
Mouse
Neurodegeneration
Synaptic Plasticity
contributor
Zimmermann, Helena (author)
Ma, Tao (committee chair)
Baker, Laura (committee member)
Furdui, Cristina (committee member)
Raab-Graham, Kimberly (committee member)
Molina, Anthony (committee member)
date
2019-05-24T08:35:37Z (accessioned)
2019 (issued)
degree
Neuroscience (discipline)
2024-05-20 (liftdate)
embargo
2024-05-20 (terms)
identifier
http://hdl.handle.net/10339/93920 (uri)
language
en (iso)
publisher
Wake Forest University
title
The Roles of AMP-Activated Protein Kinase α Isoforms in Alzheimer’s Disease
type
Dissertation

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