17 Pradhan, Ranjit Sakib, M Sadman Kaurani, Lalit Krüger, Dennis M Pena, Tonatiuh Burkhardt, Susanne Schütz, Anna-Lena Kronenberg-Versteeg, Deborah Delalle, Ivana Sananbenesi, Farahnaz Fischer, Andre AG Fischer Bioinformatics Unit (Göttingen) AG Sananbenesi AG Kronenberg-Versteeg Neurobiology of disease Neurobiology of disease Elsevier [Amsterdam] 0969-9961 10.1016/j.nbd.2026.107366 English 107366 222 Long 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. PUB:(DE-HGF)16, ; 0, ; RNA, Long Noncoding: metabolism RNA, Long Noncoding: genetics Microglia: metabolism Animals Humans Mice Trans-Activators: metabolism Trans-Activators: genetics Proto-Oncogene Proteins: metabolism Proto-Oncogene Proteins: genetics Inflammation: metabolism Inflammation: genetics Mice, Inbred C57BL Cells, Cultured Aging: metabolism Astrocytes: metabolism 3222401L13Rik/ENSG00000272070 Alzheimer's disease Long non-coding RNA (lncRNA) Microglia Neuroinflammation Non-coding RNAome PU.1 (SPI1) RNA, Long Noncoding Trans-Activators Proto-Oncogene Proteins Journal Article 2026 DZNE-2026-00385 2026 pmid:41895620 https://pub.dzne.de/record/286089 https://doi.org/10.1016/j.nbd.2026.107366