Evidence map›Paper›PMID 40275260›Full record

ArticleCell communication and signaling : CCS2025

Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability.

Victor Kumbol, Andranik Ivanov, Hugo McGurran, Jutta Schüler, Yuanyuan Zhai, Katarzyna Ludwik, Lukas Hinkelmann, Mariam Brehm, Christina Krüger, Judit Küchler and 5 more

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Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
  2. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Victor KumbolInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Andranik IvanovCore Unit Bioinformatics, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Hugo McGurranInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Jutta SchülerInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Yuanyuan ZhaiInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Katarzyna LudwikBerlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit pluripotent Stem Cells and Organoids, 13353, Berlin, Germany.
Lukas HinkelmannInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Mariam BrehmInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Christina KrügerInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Judit KüchlerBerlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit pluripotent Stem Cells and Organoids, 13353, Berlin, Germany.
Thomas WallachInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Markus HöltjeInstitute of Integrative Neuroanatomy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Dieter BeuleCore Unit Bioinformatics, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Harald StachelscheidBerlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit pluripotent Stem Cells and Organoids, 13353, Berlin, Germany.
Seija LehnardtInstitute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundDysregulation of microRNA (miRNA) expression in the brain is a common feature of neurodegenerative diseases. Beyond their conventional role in regulating gene expression at the post-transcriptional level, certain miRNAs can act extracellularly as signaling molecules. Our study elucidates the identity of such miRNA species serving as ligands for membrane receptors expressed in central nervous system (CNS) neurons and the impact of such miRNAs on neurons in the context of neurodegenerative disease.

methodsWe combined a machine learning approach with the analysis of disease-associated miRNA databases to predict Alzheimer's disease (AD)-associated miRNAs as potential signaling molecules for single-stranded RNA-sensing Toll-like receptors (TLRs) 7 and 8. TLR-expressing HEK-Blue reporter cells, primary murine microglia, and human THP-1 macrophages were used to validate the AD miRNAs as ligands for human and mouse TLR7 and/or TLR8. Interaction between mouse cortical neurons and extracellularly applied AD miRNAs was analyzed by live cell imaging and confocal microscopy. Transcriptome changes in cortical neurons exposed to AD miRNAs were assessed by RNAseq and RT-qPCR. The extracellular AD miRNAs' effects on CNS neuron structure were investigated in cell cultures of murine primary cortical neurons and iPSC-derived human cortical neurons by immunocytochemistry. We employed a mouse model of intrathecal injection to assess effects of AD miRNAs acting as signaling molecules on neurons in vivo.

resultsWe identified the AD-associated miRNAs miR-124-5p, miR-92a-1-5p, miR-9-5p, and miR-501-3p as novel endogenous ligands for TLR7 and/or TLR8. These miRNAs being extracellularly stable and active were taken up by murine cortical neurons via endocytosis and induced changes in neuronal inflammation-, proliferation-, and apoptosis-related gene expression. Exposure of both murine and human cortical neurons to the AD-associated miRNAs led to alterations of dendrite and axon structure, synapse protein expression, and cell viability in a sequence-dependent fashion. Extracellular introduction of the AD miRNAs into the cerebrospinal fluid of mice resulted in both changes in neuronal structure and synapses, and neuronal loss in the cerebral cortex. Most of the observed extracellular miRNA-induced effects on cortical neurons involved TLR7/8 signaling.

conclusionNeurodegenerative disease-associated miRNAs in extracellular form act as signaling molecules for CNS neurons including human cortical neurons, thereby modulating their structure and viability.

Indexed as

Central Nervous SystemMicroRNAsNeurodegenerative DiseasesNeuronsSignal TransductionAlzheimer DiseaseAnimalsCell SurvivalHEK293 CellsHumansMiceMicrogliaToll-Like Receptor 7Toll-Like Receptor 8MicroRNAsToll-Like Receptor 7Toll-Like Receptor 8Extracellular microRNAiPSC-derived human cortical neuronsNeurodegenerationNeuronal endocytosisToll-like receptors

Identifiers

PMID40275260
PMCPMC12020182

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.