Date of Award
8-1-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Alzheimer’s disease (AD) stands as a daunting global health challenge, affecting millions of individuals worldwide. This burden will only intensify with an aging global population. Despite significant advances in understanding AD, further exploration is needed to enhance the development of treatments and therapeutics. Particularly, I am interested in identifying the molecular pathways involved and the cell types mediating the etiology of AD. This work underscores the ability of single nucleus RNA-seq to investigate these pathways at the cell-type level and mitigate many of the hurdles limiting the successful development of treatments for AD, including genetic heterogeneity and translation of discoveries in model systems to humans. Through Genome-Wide Association Studies (GWAS), numerous critical genetic loci influencing disease risk and pathological development have been identified. However, the cell-type-specific effects of these variants remain underexplored and are yet to be effectively incorporated into clinical trials. This work leverages single-nucleus RNA sequencing (snRNA-seq) on nuclei from the understudied parietal cortex, enriched in carriers of AD risk-modifying genetic variants, to uncover the cell-type-specific effects these variants exert on neurons and glia. Specifically, this work identified similar, but more extreme gene expression shifts in autosomal dominant AD (ADAD) than in sporadic AD (sAD) compared to controls. It also highlights microglia and oligodendrocyte expression states associated TREM2 variant carriers and an altered activated microglia state associated with a protective variant in the MS4A cluster. Experimental models offer the advantage of controlled environments that allow for the isolation of specific variables, providing clearer insights into the mechanisms underlying AD pathology. Combining these models with human data enhances the translatability of the finding to the human condition. This research also integrates human microglia snRNA-seq data with mouse microglia single-cell RNA sequencing (scRNA-seq) data, demonstrating that microglia from mice with ablated lymphatics cluster more frequently with activated human microglia. This finding underscores the pivotal role of lymphatics in disease outcomes and successful antibody treatments. The study also reveals common Single Nucleotide Polymorphisms (SNPs) in the human population that influence the expression of critical Lymphatic Endothelial Cell (LEC) genes, thereby impacting AD pathology and treatment responses in humans. Understanding Gene Regulatory Networks (GRNs) is crucial for elucidating the complex interactions between genes and their regulatory elements, which ultimately govern cell function and disease progression. This research leverages microglia and astrocyte snRNA-seq data to understand the cell-state-specific GRNs for APOE, revealing a link between APOE expression and the circadian rhythm. This work highlights that a single gene can contribute to different functional systems depending on the cell type, suggesting that therapeutics targeting the expression of specific genes could yield cell-type-specific outcomes. In conclusion, this work highlights the power of snRNA-seq in addressing challenges in the successful development of therapeutic interventions for AD. It emphasizes the importance of uncovering the genetic heterogeneity driving disease subclasses and the need for translating discoveries from mouse model systems to the human condition.
Language
English (en)
Chair and Committee
Oscar Harari
Committee Members
Celeste Karch; Bruno Benitez; Gabe Haller; Joseph Dougherty; Nancy Saccone
Recommended Citation
Brase, Logan, "Employing Single-Nucleus RNA-Seq to Uncover Genetic Factors of Alzheimer Disease" (2024). Arts & Sciences Electronic Theses and Dissertations. 3283.
https://openscholarship.wustl.edu/art_sci_etds/3283