Advisory Committee Chair
Brittany Lasseigne
Advisory Committee Members
Constanza Cortes
Jeremy Herskowitz
John Parant
Melissa Harris
Steven Austad
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Alzheimer’s disease is the most prevalent neurodegenerative disease and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology includes the formation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles of phosphorylated tau. Additionally, neurons become functionally impaired before degenerating and dying. While neuronal loss is a disease hallmark, glia maintain neuronal health and homeostasis through cell-cell communication with neurons. Cellular crosstalk is mediated through the release of chemical intermediates (i.e., ligands), which are taken up by cell surface membrane receptors. Previous studies have shown dysregulation of global cell-cell communication patterns and communication between neurons and glia, but whether glia-neuron communication is altered and its downstream effects in neurons remain understudied in Alzheimer’s disease. Therefore, to determine whether cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, OPCs) and neurons (excitatory and inhibitory) is altered, we inferred ligands, receptors, and downstream target genes using snRNA-seq data from the postmortem human prefrontal cortex of Alzheimer’s patients as well as hippocampal tissues from 3xTg-AD mice, which exhibit amyloid and tau pathology, from two time points to evaluate cellular crosstalk throughout disease progression. In the postmortem human prefrontal cortex, we identified and validated 54 differentially expressed ligand-receptor pairs, which included the Alzheimer’s disease risk genes APP and APOE. Additionally, intracellular signaling mediators and target genes in neurons were associated with the canonical signaling pathways WNT, p53, and NFkB. To identify changes in glia-neuron communication throughout disease progression, I generated snRNA-seq data from 6- and 12-month-old 3xTg-AD and wild-type mice. I found increased cellular crosstalk dysregulation at 12 months in 3xTg-AD mice. Additionally, using gene regulatory network, functional enrichment, and biological activity analyses, I identified changes in gene regulation downstream of ligand-receptor pairs that had an Alzheimer’s disease risk gene as a downstream target in 3xTg-AD mice. Together, the results presented in this dissertation demonstrate that glia-neuron communication is altered in the postmortem human prefrontal cortex in Alzheimer’s disease and is increasingly dysregulated throughout disease progression in the 3xTg-AD mouse model. Finally, my work reveals downstream gene regulatory consequences of altered glia-neuron communication in excitatory and inhibitory neurons.
Recommended Citation
Soelter, Tabea Marga, "The Role Of Altered Cell-Cell Communication Between Glia And Neurons In Alzheimer’S Disease" (2025). All ETDs from UAB. 6889.
https://digitalcommons.library.uab.edu/etd-collection/6889
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