Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease

dc.contributor.authorXu, Jielin
dc.contributor.authorZhang, Pengyue
dc.contributor.authorHuang, Yin
dc.contributor.authorZhou, Yadi
dc.contributor.authorHou, Yuan
dc.contributor.authorBekris, Lynn M.
dc.contributor.authorLathia, Justin
dc.contributor.authorChiang, Chien-Wei
dc.contributor.authorLi, Lang
dc.contributor.authorPieper, Andrew A.
dc.contributor.authorLeverenz, James B.
dc.contributor.authorCummings, Jeffrey
dc.contributor.authorCheng, Feixiong
dc.contributor.departmentBiostatistics and Health Data Science, School of Medicine
dc.date.accessioned2024-04-15T11:16:28Z
dc.date.available2024-04-15T11:16:28Z
dc.date.issued2021
dc.description.abstractBecause disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P < 1.0 × 10-8). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P < 1.0 × 10-8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD.
dc.eprint.versionFinal published version
dc.identifier.citationXu J, Zhang P, Huang Y, et al. Multimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease. Genome Res. 2021;31(10):1900-1912. doi:10.1101/gr.272484.120
dc.identifier.urihttps://hdl.handle.net/1805/39972
dc.language.isoen_US
dc.publisherCold Spring Harbor Laboratory
dc.relation.isversionof10.1101/gr.272484.120
dc.relation.journalGenome Research
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.sourcePMC
dc.subjectAlzheimer disease
dc.subjectAstrocytes
dc.subjectDrug repositioning
dc.subjectMicroglia
dc.titleMultimodal single-cell/nucleus RNA sequencing data analysis uncovers molecular networks between disease-associated microglia and astrocytes with implications for drug repurposing in Alzheimer's disease
dc.typeArticle
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