Transcriptomic Signatures of Cognitive Impairment

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dc.contributor.advisorPhillips, Nicole R.
dc.contributor.committeeMemberBarber, Robert C.
dc.contributor.committeeMemberPlanz, John V.
dc.contributor.committeeMemberNejtek, Vicki
dc.contributor.committeeMemberRickards, Caroline A.
dc.creatorSilzer, Talisa K.
dc.creator.orcid0000-0002-8894-0368 (Silzer, Talisa K.)
dc.date.accessioned2021-12-16T21:15:12Z
dc.date.available2021-12-16T21:15:12Z
dc.date.issued2020-08
dc.description.abstractThe dramatic shift in population demographics and rapid growth of the aging population has resulted in a drastic increase in the prevalence of complex age-related diseases. Of the most common age-related complex diseases, Alzheimer's disease (AD) remains the primary cause of dementia. The increased prevalence of this disease presents a major burden on our healthcare system and caregivers. Among the many pathophysiological hallmarks, there is a substantial amount of literature implicating mitochondrial dysfunction as an important signature of early AD pathophysiology. Use of 'omics' technologies and system-based approaches have become increasingly more common for studying AD. Though each data type (i.e. genomics, transcriptomics and proteomics) has advantages and disadvantages, transcriptomics serves as a cost-efficient method for obtaining a snapshot of functional molecular changes underlying the disease. Here we detail two distinct and innovative studies of the transcriptome using different analytical strategies to investigate the underlying molecular signatures of cognitive impairment in its varying forms. We report the first study of differential gene expression in mild cognitively impaired Mexican Americans. This study revealed 30 differentially expressed transcripts that were enriched for a number of biological processes previously implicated in AD pathophysiology. The second study is also the first of its kind (in the context of this phenotype) examining posttranscriptional methylation at functionally important sites within the mitochondrial transcriptome of individuals diagnosed with AD, progressive supranuclear palsy (PSP) or pathological aging(PA). We observed similar hypermethylation at these key sites in individuals diagnosed with tauopathies such as AD or PSP. Several nuclear-encoded genes were identified as associated and the expression of 5300 nuclear-encoded transcripts was correlated with this hypermethylation. These correlated transcripts were enriched for a number of biological and molecular processes. Though these studies are quite distinct in methodology, we observed overlap in the enriched processes identified in each respective study (i.e. mitochondrial dysfunction, chromatin binding/remodeling, protein degradation pathways, autophagy); many of these processes have been previously implicated in AD. Replication of these findings in larger cohorts and different racial/ethnic populations will be vital for gaining a more complete understanding of the molecular dysfunction that underlies cognitive impairment phenotypes.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/30770
dc.language.isoen
dc.subjectRNA
dc.subjectAlzheimer's disease
dc.subjectMCI
dc.subjectmitochondria
dc.subject.meshAlzheimer Disease / physiopathology
dc.subject.meshMitochondria
dc.subject.meshCognitive Dysfunction
dc.titleTranscriptomic Signatures of Cognitive Impairment
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineNeurobiology of Aging
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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