TY  - JOUR
AU  - McGurran, Hugo
AU  - Graceffo, Eugenio
AU  - Kumbol, Victor
AU  - Jendrach, Marina
AU  - Hinkelmann, Lukas
AU  - Brehm, Mariam
AU  - Ravatt, Leandre
AU  - Krüger, Christina
AU  - Wallach, Thomas
AU  - Haake, Alexander
AU  - Wegmann, Susanne
AU  - Heppner, Frank L
AU  - Schülke, Markus
AU  - Lehnardt, Seija
TI  - MicroRNA-29a-5p contributes to neuroinflammation through TLR7.
JO  - Journal of neuroinflammation
VL  - 23
IS  - 1
SN  - 1742-2094
CY  - London
PB  - BioMed Central
M1  - DZNE-2026-00119
SP  - 38
PY  - 2026
AB  - MicroRNAs (miRNAs) canonically regulate post-transcriptional gene expression, but they can also serve as ligands for Toll-like receptors (TLRs). These receptors and their associated signalling pathways contribute to inflammatory responses involved in various central nervous system (CNS) diseases, including Alzheimer's disease (AD). Here, we investigated the effects of extracellularly delivered miRNA in the context of neuroinflammation. We identified several miRNAs specifically dysregulated in AD and/or neuroinflammatory states, which directly activate the single-stranded RNA sensors mouse TLR7 and human TLR7/8. Among them, extracellular miR-29a-5p induced cytokine and chemokine release from murine primary microglia, altered expression of TLR signalling elements, and enhanced Aβ phagocytosis. Furthermore, this miRNA induced neuronal injury dependent on microglial TLR7 expression, but also in a cell-autonomous fashion, in vitro. Intrathecal injection of miR-29a-5p into mice led to microglial accumulation and neuronal injury in the cerebral cortex through TLR7 after 3 days. Brains of wild-type and APP/PS1 mice, an established AD mouse model, treated with multiple intrathecal miR-29a-5p injections over 120 days exhibited changes in cytokine/chemokine expression and neuronal injury. RNAseq analysis of the cerebral cortex of both miRNA-treated genotypes revealed downregulation of MAPK-associated pathways.Our study establishes AD-associated miRNAs such as miR-29a-5p as TLR7 agonists and signalling molecules for microglia, thereby altering the neuroinflammatory response.
KW  - Animals
KW  - MicroRNAs: metabolism
KW  - MicroRNAs: genetics
KW  - MicroRNAs: administration & dosage
KW  - Toll-Like Receptor 7: metabolism
KW  - Toll-Like Receptor 7: genetics
KW  - Mice
KW  - Neuroinflammatory Diseases: metabolism
KW  - Neuroinflammatory Diseases: genetics
KW  - Neuroinflammatory Diseases: pathology
KW  - Humans
KW  - Microglia: metabolism
KW  - Mice, Transgenic
KW  - Mice, Inbred C57BL
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: genetics
KW  - Membrane Glycoproteins: metabolism
KW  - Membrane Glycoproteins: genetics
KW  - Cells, Cultured
KW  - Male
KW  - Alzheimer’s disease (Other)
KW  - Cytokine expression (Other)
KW  - MicroRNA (Other)
KW  - Microglia (Other)
KW  - Neuroinflammation (Other)
KW  - Toll-like receptors (Other)
KW  - MicroRNAs (NLM Chemicals)
KW  - Toll-Like Receptor 7 (NLM Chemicals)
KW  - Tlr7 protein, mouse (NLM Chemicals)
KW  - MIRN29 microRNA, mouse (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - MIRN29a microRNA, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41514337
C2  - pmc:PMC12849500
DO  - DOI:10.1186/s12974-025-03680-4
UR  - https://pub.dzne.de/record/284348
ER  -