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The neuropathology of AD includes the formation of extracellular amyloid\u2010\u03b2 plaques and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. Although neuronal loss is an AD hallmark, cell\u2013cell communication between neuronal and non\u2010neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cell\u2013cell communication during disease progression, we performed snRNA\u2010sequencing of the hippocampus from female 3xTg\u2010AD and wild\u2010type littermates at 6 and 12\u00a0months. We inferred differential cell\u2013cell communication between 3xTg\u2010AD and wild\u2010type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia\u2013neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia\u2013neuron communication is increasingly dysregulated in 12\u2010month 3xTg\u2010AD mice. We also identified 23 AD\u2010associated ligand\u2013receptor pairs that are upregulated in the 12\u2010month\u2010old 3xTg\u2010AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and transcription factor activity. Our findings indicate that altered glia\u2013neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12\u2010month\u2010old 3xTg\u2010AD mice.<\/jats:p>","DOI":"10.1002\/ccs3.70006","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T22:55:41Z","timestamp":1741647341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of altered cell\u2013cell communication between glia and neurons in the hippocampus of 3xTg\u2010AD mice at two time points"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1654-4240","authenticated-orcid":false,"given":"Tabea M.","family":"Soelter","sequence":"first","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology Heersink School of Medicine The University of Alabama at Birmingham  Birmingham Alabama 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