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Altered glia-neuron communication in Alzheimer’s Disease affects WNT, p53, and NFkB Signaling determined by snRNA-seq

dc.contributor.authorTabea M. Soelter
dc.contributor.authorTimothy C. Howton
dc.contributor.authorAmanda D. Clark
dc.contributor.authorVishal H. Oza
dc.contributor.authorBrittany N. Lasseigne
dc.contributor.otherDepartment of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham
dc.contributor.otherDepartment of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham
dc.contributor.otherDepartment of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham
dc.contributor.otherDepartment of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham
dc.contributor.otherDepartment of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham
dc.date.accessioned2024-06-09T11:27:23Z
dc.date.accessioned2025-10-08T08:06:50Z
dc.date.available2025-10-08T08:06:50Z
dc.date.issued2024-06
dc.identifier.urihttp://digilib.fisipol.ugm.ac.id/repo/handle/15717717/35598
dc.description.abstractAbstract Background Alzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons. Methods Using public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons. Results Cell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer’s disease risk genes APP and APOE across datasets. Most of the signaling mediators of these interactions were not significantly differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer’s disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity of NFIL3, an NFkB signaling-associated transcription factor. Conclusions Cell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.
dc.language.isoEN
dc.publisherBMC
dc.subject.lccMedicine
dc.titleAltered glia-neuron communication in Alzheimer’s Disease affects WNT, p53, and NFkB Signaling determined by snRNA-seq
dc.typeArticle
dc.description.keywordsAlzheimer’s disease
dc.description.keywordsNeurodegeneration
dc.description.keywordsCell-cell communication
dc.description.keywordsSignaling
dc.description.keywordsSingle-cell
dc.description.keywordsNetworks
dc.description.pages1-16
dc.description.doi10.1186/s12964-024-01686-8
dc.title.journalCell Communication and Signaling
dc.identifier.e-issn1478-811X
dc.identifier.oai8bb2bd0ed74f487fb8fd59b64dc9c11c
dc.journal.infoVolume 22, Issue 1


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