All ETDs from UAB

Advisory Committee Chair

John David Sweatt

Advisory Committee Members

Sarah Clinton

Jeremy Day

Robin Lorenz

Michelle Olsen

Erik Roberson

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The ability to encode information for long-term behavioral adaptation relies on experience-dependent alterations in neuronal plasticity. Neuronal plasticity encompasses the cellular and molecular changes that modulate synaptic communication between neurons as well as intrinsic electrophysiological properties within neurons. Epigenetic mechanisms, including DNA cytosine methylation and histone post-translational modifications, are powerful regulators of neuronal gene expression, allowing for dynamic, bidirectional regulation of transcriptional signatures necessary for neuronal plasticity. Emerging evidence using candidate-gene and microarray-based approaches suggest that the deficits in neuronal plasticity and cognitive impairment observed in Alzheimer’s disease (AD) is attributable, in part, to aberrant cytosine methylation and transcription of genes involved in cell signaling, inflammation, and neurotransmission. The work presented in this dissertation goes beyond previous attempts by using cutting-edge, next-generation sequencing technologies to systematically characterize genome-wide alterations in gene expression and DNA methylation in hAPP(J20) mice, an amyloid-beta (Aβ) over-expressing mouse model of AD. Hippocampal Aβ-deposition was associated with widespread transcriptional dysregulation, targeting, in particular, genes implicated in extracellular matrix restructuring and immune function as well as chromatin biology and neuronal plasticity. In contrast, Aβ-deposition was associated with fewer alterations in DNA methylation, enriched, however, at genes linked to transcriptional regulation and neuronal differentiation. Most notably, the work in this dissertation utilizes an integrative transcriptomic meta-analysis in combination with network analyses to identify the histone deacetylase, HDAC2, as a conserved therapeutic target of interest and validates the use of anti-sense oligonucleotide mediated knockdown of HDAC2 as a viable treatment for AD-related cognitive impairment. Thus, the findings presented here provide additional evidence in support of AD-related transcriptional and epigenetic dysregulation and provide a new framework by which to investigate and treat Aβ-associated cognitive impairment.

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