ID: h-cae1ad2e
Hypothesis
Astrocyte-Derived EV miR-146a-5p Mimics as Erasers of Trained Microglial NF-κB Memory
AEVs containing miR-146a-5p are taken up by microglia and suppress IRAK1/TRAF6, disrupting sustained NF-κB activation that maintains pathological memory.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 3 oppose
✓ All Quality Gates Passed
🧪 Overview
AEVs containing miR-146a-5p are taken up by microglia and suppress IRAK1/TRAF6, disrupting sustained NF-κB activation that maintains pathological memory. miR-146a also targets NOTCH1 and HDAC1, restoring repressive histone marks at previously trained enhancer regions. The mechanism has strong conceptual support from peripheral trained immunity studies but faces significant in vivo delivery challenges.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["miR-146a-5p to IRAK1, TRAF6, NOTCH1, HDAC1<br/>Hypothesis Target"]
B["Microglial<br/>Cited Mechanism"]
C["Cellular Response<br/>Stress or Clearance Change"]
D["Neural Circuit Effect<br/>Synapse/Glia Vulnerability"]
E["ALS<br/>Disease-Relevant Outcome"]
A --> B
B --> C
C --> D
D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix3 supports3 contradicts
Supports
miR-146a delivered via mesenchymal stem cell EVs reduces neuroinflammation in stroke
Contradicts
AEV uptake by parenchymal microglia in intact brain has minimal direct evidence
Contradicts
Anti-inflammatory AEV effect required direct cell contact in some conditions
Contradicts
miR-146a is inflammation-inducible; microglia already upregulate it during trained response (ceiling effects)
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MIR-146A-5P
No curated PDB or AlphaFold mapping for MIR-146A-5P yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for miR-146a-5p → IRAK1, TRAF6, NOTCH1, HDAC1 from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for miR-146a-5p → IRAK1, TRAF6, NOTCH1, HDAC1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary adult mouse microglia with established trained immunity (induced by 100 ng/mL LPS for 24h, then rested 72h, then restimulated) are treated with 50 nM miR-146a-5p mimic (transfected with Lip | H3K27ac ChIP-qPCR at NF-κB p65-bound enhancer regions (identified by prior ChIP-seq) will show significant enrichment increase in miR-146a-5p mimic-treated micr | — no observation — | pending | 0.55 |
| IF adult C57BL/6J mice with established LPS-induced trained microglia receive intranasal administration of astrocyte-derived extracellular vesicles enriched for miR-146a-5p (100 μg total protein, 3 do | NF-κB p65 DNA-binding activity (assessed by ELISA-based TransAM assay) will show statistically significant reduction (p < 0.05) in the miR-146a-5p AEV treatment | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF adult C57BL/6J mice with established LPS-induced trained microglia receive intranasal administration of astrocyte-derived extracellular vesicles enriched for miR-146a-5p (100 μg total protein, 3 doses over 7 days), THEN nuclear NF-κB p65 DNA-binding activity in isolated CD11b+ microglia will decr
Predicted outcome: NF-κB p65 DNA-binding activity (assessed by ELISA-based TransAM assay) will show statistically significant reduction (p < 0.05) in the miR-146a-5p AEV
Falsification: NF-κB p65 DNA-binding activity remains within 20% of vehicle control levels (≤0.20% change from baseline) despite miR-146a-5p AEV administration, or alternatively, mRNA expression of downstream NF-κB
pendingconf 55%
IF primary adult mouse microglia with established trained immunity (induced by 100 ng/mL LPS for 24h, then rested 72h, then restimulated) are treated with 50 nM miR-146a-5p mimic (transfected with Lipofectamine RNAiMAX) compared to scrambled miRNA control, THEN H3K27ac occupancy at previously traine
Predicted outcome: H3K27ac ChIP-qPCR at NF-κB p65-bound enhancer regions (identified by prior ChIP-seq) will show significant enrichment increase in miR-146a-5p mimic-tr
Falsification: H3K27ac levels at trained Il1b/Tnf enhancer regions show no significant change (≤1.2-fold) or decrease relative to scrambled control, or HDAC1 protein levels remain within 80% of control levels, indic
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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