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The Gene Expression Landscape of Alzheimer’s Disease Tauopathy and Selective Vulnerability

Ayoub, Christopher Anthony
http://orcid.org/0000-0003-0694-1058
http://rave.ohiolink.edu/etdc/view?acc_num=osu1680166146871177

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Alzheimer’s Disease (AD) is a debilitating neurodegenerative disorder characterized by the progressive and selective accumulation of neurofibrillary tangles in specific areas of the brain over the course of disease. Composed of aggregated tau protein, these tangles appear to spread from the earliest affected regions to networked brain regions across the synapse, templating additional pathology in a prion-like manner. However, the cerebellum appears to resist this prion-like insult, despite connectivity to early and profoundly affected regions. The selective vulnerability and resistance of specific brain regions and cell types to prion-like tau pathology offers a window into disease etiology and endogenous mechanisms of neuroprotection. The objective of this work was to untangle the adaptive changes to disease that respond in parallel and in contrast between differentially vulnerable tissues to provide new insight into disease etiology and new targets for biological validation in disease models. First, we define a unique gene expression approach termed Ratio of Ratios that tests differential gene expression across AD and control in the vulnerable prefrontal cortex and the resistant cerebellum. We apply this along with Desirability Function Analysis to a publicly available microarray data set to sort genes into priority groups demonstrating contrasting differential expression between regions that associates with selective vulnerability, and parallel differential expression between regions that is nonspecific to vulnerability. Among contrasting genes, we find a neuronal and endothelial proteostasis signature where chaperones are selectively upregulated in the cerebellum. Among parallel genes, we find a microglial, astrocytic, and endothelial signature of immune and stress activation. Using transcription factor interaction network analysis, we report potential key regulators of these contrasting and parallel responses. We also show that the identified chaperone proteins successfully antagonize tau aggregation in vitro. Building on this, we next tested the replicability of these findings in an independent transcriptomic data set to determine the generalizability of our conclusions. We found a strong correlation of the Ratio of Ratios metric between data sets, as well as strong overlap in prioritization when using relaxed criteria. Enrichment analysis of the priority sets defined independently between data sets demonstrated both replicated and non-replicated cell type specific markers and biological processes. Replicated contrasting upregulated processes again include proteostasis genes, but also include cell trafficking, implying a role for endocytosis and secretion of prion-like seeds. Using weighted gene coexpression network analysis, we report modules enriched for contrasting up and downregulated gene sets, as well as their top hubs. Finally, we extend this approach to a disease comparison between AD and Progressive Supranuclear Palsy, a distinct tauopathy where the cerebellum is indeed vulnerable. There we find predominantly parallel biological processes, including proteostasis, but again we identify enrichment of cell trafficking genes in the contrasting downregulated gene set. Altogether we provide a comprehensive view of the gene expression landscape in AD with a unique lens for selective vulnerability. This work generates numerous testable hypotheses for mechanistic studies in disease models of prion-like propagation that will move the field forward.
Jeffrey Kuret (Advisor)
Karl Obrietan (Committee Member)
Andrea Tedeschi (Committee Member)
Hongjun Fu (Committee Member)
191 p.
Bioinformatics; Biology; Biomedical Research; Neurosciences
Alzheimer's Disease; neurodegeneration; tau protein; tauopathy; prion; gene expression; transcriptomics; bioinformatics; selective vulnerability

Recommended Citations

Citations

  • Ayoub, C. A. (2023). The Gene Expression Landscape of Alzheimer’s Disease Tauopathy and Selective Vulnerability [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1680166146871177

    APA Style (7th edition)

  • Ayoub, Christopher. The Gene Expression Landscape of Alzheimer’s Disease Tauopathy and Selective Vulnerability. 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1680166146871177.

    MLA Style (8th edition)

  • Ayoub, Christopher. "The Gene Expression Landscape of Alzheimer’s Disease Tauopathy and Selective Vulnerability." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1680166146871177

    Chicago Manual of Style (17th edition)

osu1680166146871177
174
© 2023, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.