engPradhan, RanjitSakib, M SadmanFischer, AndreKaurani, LalitKrüger, Dennis MPena, TonatiuhBurkhardt, SusanneSchütz, Anna-LenaKronenberg-Versteeg, DeborahDelalle, IvanaSananbenesi, FarahnazlncRNA Glelr modulates microglia inflammatory programs in association with PU.1.info:eu-repo/classification/ddc/570RNA, Long Noncoding: metabolismRNA, Long Noncoding: geneticsMicroglia: metabolismAnimalsHumansMiceTrans-Activators: metabolismTrans-Activators: geneticsProto-Oncogene Proteins: metabolismProto-Oncogene Proteins: geneticsInflammation: metabolismInflammation: geneticsMice, Inbred C57BLCells, CulturedAging: metabolismAstrocytes: metabolism3222401L13Rik/ENSG00000272070Alzheimer's diseaseLong non-coding RNA (lncRNA)MicrogliaNeuroinflammationNon-coding RNAomePU.1 (SPI1)RNA, Long NoncodingTrans-ActivatorsProto-Oncogene ProteinsLong non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA Glelr as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog GLELR. We found that Glelr/GLELR is expressed in both astrocytes and microglia and increases with age. Knockdown of Glelr in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNFα, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog GLELR showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, Glelr interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, GLELR expression was significantly reduced in postmortem Alzheimer's disease (AD) brains, and AD-associated genes were enriched among Glelr-regulated targets. Together, our results identify Glelr/GLELR as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests GLELR as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases.Neurobiology of disease 222, 107366 (2026). doi:10.1016/j.nbd.2026.107366info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionElsevier2026info:eu-repo/semantics/closedAccessDEhttps://pub.dzne.de/record/286089https://pub.dzne.de/search?p=id:%22DZNE-2026-00385%22Researchersinfo:eu-repo/semantics/altIdentifier/pmid/pmid:41895620info:eu-repo/semantics/altIdentifier/issn/1095-953Xinfo:eu-repo/semantics/altIdentifier/issn/0969-9961info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2026.107366