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MicroRNA-100-5p and microRNA-298-5p released from apoptotic cortical neurons are endogenous Toll-like receptor 7/8 ligands that contribute to neurodegeneration
Abstract
Background: MicroRNA (miRNA) expression in the brain is altered in neurodegenerative diseases. Recent studies demonstrated that selected miRNAs conventionally regulating gene expression at the post-transcriptional level can act extracellularly as signaling molecules. The identity of miRNA species serving as membrane receptor ligands involved in neuronal apoptosis in the central nervous system (CNS), as well as the miRNAs’ sequence and structure required for this mode of action remained largely unresolved. Methods: Using a microarray-based screening approach we analyzed apoptotic cortical neurons of C56BL/6 mice and their supernatant with respect to alterations in miRNA expression/presence. HEK-Blue Toll-like receptor (TLR) 7/8 reporter cells, primary microglia and macrophages derived from human and mouse were employed to test the potential of the identified miRNAs released from apoptotic neurons to serve as signaling molecules for the RNA-sensing receptors. Biophysical and bioinformatical approaches, as well as immunoassays and sequential microscopy were used to analyze the interaction between candidate miRNA and TLR. Immunocytochemical and -histochemical analyses of murine CNS cultures and adult mice intrathecally injected with miRNAs, respectively, were performed to evaluate the impact of miRNA-induced TLR activation on neuronal survival and microglial activation. Results: We identified a specific pattern of miRNAs released from apoptotic cortical neurons that activate TLR7 and/or TLR8, depending on sequence and species. Exposure of microglia and macrophages to certain miRNA classes released from apoptotic neurons resulted in the sequence-specific production of distinct cytokines/chemokines and increased phagocytic activity. Out of those miRNAs miR-100-5p and miR-298-5p, which have consistently been linked to neurodegenerative diseases, entered microglia, located to their endosomes, and directly bound to human TLR8. The miRNA-TLR interaction required novel sequence features, but no specific structure formation of mature miRNA. As a consequence of miR-100-5p- and miR-298-5p-induced TLR activation, cortical neurons underwent cell-autonomous apoptosis. Presence of miR-100-5p and miR-298-5p in cerebrospinal fluid led to neurodegeneration and microglial accumulation in the murine cerebral cortex through TLR7 signaling. Conclusion: Our data demonstrate that specific miRNAs are released from apoptotic cortical neurons, serve as endogenous TLR7/8 ligands, and thereby trigger further neuronal apoptosis in the CNS. Our findings underline the recently discovered role of miRNAs as extracellular signaling molecules, particularly in the context of neurodegeneration.
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A second group of 60 candidate miRNAs was identified by re-analyzing previously published small RNA sequencing and microarray data derived from apoptotic cortical neurons releasing miRNAs.
“Out of the miRNAs with dysregulated expression in AD a second group of 60 candidate miRNAs was identified by re-analyzing previously published small RNA sequencing and microarray data derived from apoptotic cortical neurons releasing miRNAs [20, 33].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Neurons exposed to certain miRNAs undergo cell death through TLR7.
“We have shown previously that neurons exposed to certain miRNAs undergo cell death through TLR7 [4, 20].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Certain extracellular miRNAs, such as let-7b, induce neuronal cell death.
“Certain extracellular miRNAs, such as let-7b, induce neuronal cell death [4, 20].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Neurons express ssRNA-sensing TLRs in endosomes.
“Neurons express ssRNA-sensing TLRs in endosomes [4, 5, 20].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Cell injury is a central effect of miRNAs acting as signaling molecules in the CNS.
“This is in line with previous studies investigating other miRNAs, such as let-7b [4, 20], and point to cell injury as a central effect of miRNAs acting as signaling molecules in the CNS.”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
In contrast to microglia and macrophages, whose response to extracellular miRNA requires complexation with cationic lipids, cortical neurons internalized miRNA without transfection.
“In contrast to microglia and macrophages, whose response to extracellular miRNA requires complexation with cationic lipids [4, 6, 20], cortical neurons internalized miRNA without transfection.”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
miR-92a-1-5p and miR-124-5p, whose expression is downregulated in apoptotic neurons, in their extracellular form induced injury of cortical neurons via TLR7 and caspase-3.
“miR-92a-1-5p and miR-124-5p, whose expression is downregulated in apoptotic neurons [20, 33], in their extracellular form induced injury of cortical neurons via TLR7 and caspase-3.”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Cerebrospinal fluid of AD patients contains miRNAs, which are released from apoptotic neurons and are capable of neuronal injury.
“cerebrospinal fluid of AD patients contains miRNAs, which are released from apoptotic neurons and are capable of neuronal injury [4, 20].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Such miRNAs bind to human TLR8.
“Using microscale thermophoresis we confirmed that such miRNAs bind to human TLR8 [20].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
miR-100-5p and miR-298-5p directly activate TLR7/8 and localize to TLR7 and endosomes in murine microglia.
“We have demonstrated in previous work that miR-100-5p and miR-298-5p, which directly activate TLR7/8, localize to TLR7 and endosomes in murine microglia [20].”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
Injured neurons release miRNAs, which being stably present in the extracellular space can act as signaling molecules on neighboring neurons, thereby triggering neurodegeneration.
“Based on our previous [4, 20] and current data we suggest a mechanism whereby injured neurons release miRNAs, which - being stably present in the extracellular space - can act as signaling molecules on neighboring neurons, thereby triggering neurodegeneration.”
From Neurodegenerative disease-associated microRNAs acting as signaling molecules modulate CNS neuron structure and viability (2025) · cites this paper as [20]
miR-100-5p released from apoptotic cortical neurons activates endogenous Toll-like receptors 7/8 (TLR7/8) and serves as their ligand to trigger further neuronal apoptosis that contributes to neurodegeneration.
“Studies have shown, the miR-100-5p released from apoptotic cortical neurons activates endogenous Toll-like receptors 7/8 (TLR7/8) and serves as their ligand to trigger further neuronal apoptosis that contributes to neurodegeneration [7].”
From Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage (2025) · cites this paper as [7]
In the CNS, miR-100-5p released from apoptotic cortical neurons can activate endogenous TLR7/8 to trigger further neuronal apoptosis.
“In the CNS, miR-100-5p released from apoptotic cortical neurons can activate endogenous TLR7/8 to trigger further neuronal apoptosis [7].”
From Engineered Extracellular Vesicles Loaded with MiR-100-5p Antagonist Selectively Target the Lesioned Region to Promote Recovery from Brain Damage (2025) · cites this paper as [7]
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Cited by
Sorted by citations
Kumbol, V., Ivanov, A., McGurran, H., Schüler, J., Zhai, Y., Ludwik, K., Hinkelmann, L., Brehm, M., Krüger, C., Küchler, J., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02199-8 · Cited by 8
Self-citationCheng, Y., Gai, C., Zhao, Y., Li, T., Song, Y., Luo, Q., Xin, D., Jiang, Z., Chen, W., Liu, D., et al. (2025) · Neuroscience Bulletin · doi:10.1007/s12264-025-01376-6 · Cited by 5
Metadata
- Authors
- Wallach, T., Mossmann, Z. J., Szczepek, M., Wetzel, M., Machado, R., Raden, M., Miladi, M., Kleinau, G., Krüger, C., Dembny, P., Adler, D., Zhai, Y., Kumbol, V., Dzaye, O., Schüler, J., Futschik, M., Backofen, R., Scheerer, P., & Lehnardt, S.
- ORCID
- Lehnardt, Seija
- Venue
- Molecular Neurodegeneration
- Published
- 2021-11-27
- Volume
- 16
- Issue
- 1
- ISSN
- 1750-1326
- PMC
- PMC8626928
- Cited by
- 48
- References
- 9
- Language
- en
- Funders
- deutsche forschungsgemeinschaft (NeuroCure Exc 257, LE 2420/2-1, SFB-TRR 167/B03, BA 2168/16-1, BA 2168/21-1, BA 2168/3-3, CRC 1078/B6, CRC 1423)
- germany‘s excellence strategy (CIBSS-EXC-2189-Project ID 390939984)
- Charité - Universitätsmedizin Berlin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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