Version history

{
  "description": "Microglia activate astrocytes via IL-1alpha/TNF/C1q, and reactive astrocytes feed back to microglia via complement/chemokines.",
  "domain": "neurodegeneration",
  "status": "partially_addressed",
  "priority_score": 0.89,
  "importance_score": 0.88,
  "tractability_score": 0.75,
  "novelty_score": 0.65,
  "composite_score": 0.6856,
  "source": "agent_generated",
  "evidence_summary": "{\"hypothesis_matches\": [{\"id\": \"h-var-e47f17ca3b\", \"title\": \"Beta-frequency entrainment therapy targeting PV interneuron-astrocyte coupling for tau clearance\", \"target_gene\": \"SST\", \"target_pathway\": \"Astrocyte-glymphatic tau clearance via AQP4 and beta-frequency interneuron gating\", \"match_score\": 0.37, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-89500d80\", \"title\": \"Astrocyte-Microglia Communication Rebalancing via Cytokine Modulation\", \"target_gene\": \"IL1A, TNF, C1Q\", \"target_pathway\": null, \"match_score\": 0.34, \"composite_score\": 0.4881217569068229, \"status\": \"proposed\"}, {\"id\": \"h-cc1076c1\", \"title\": \"Cardiovascular-Neuroinflammation Crosstalk Interruption\", \"target_gene\": \"IL1B, TNFA, NLRP3\", \"target_pathway\": null, \"match_score\": 0.27, \"composite_score\": 0.4471687073585568, \"status\": \"proposed\"}, {\"id\": \"h-var-d98a992599\", \"title\": \"Closed-loop tACS targeting entorhinal cortex layer II SST interneurons to activate AMPK-autophagy flux and degrade intracellular tau before exosomal packaging in Alzheimer's disease\", \"target_gene\": \"SST\", \"target_pathway\": \"Entorhinal cortex layer II SST interneuron-driven GABAergic hyperpolarization activating AMPK-ULK1-beclin-1 autophagy flux to degrade tau oligomers before exosomal trans-synaptic propagation to hippocampus\", \"match_score\": 0.27, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-58e4635a\", \"title\": \"SASP-Mediated Complement Cascade Amplification\", \"target_gene\": \"C1Q/C3\", \"target_pathway\": \"C1q / complement-mediated synapse elimination\", \"match_score\": 0.24, \"composite_score\": 0.64439022819055, \"status\": \"proposed\"}, {\"id\": \"h-seaad-56fa6428\", \"title\": \"GFAP-Positive Reactive Astrocyte Subtype Delineation\", \"target_gene\": \"GFAP\", \"target_pathway\": \"Astrocyte Reactivity / A1-A2 Polarization\", \"match_score\": 0.24, \"composite_score\": 0.502924359089148, \"status\": \"proposed\"}, {\"id\": \"h-var-adfecef68a\", \"title\": \"Astrocyte-Intrinsic NLRP3 Inflammasome Activation by Alpha-Synuclein Aggregates Drives Non-Cell-Autonomous Neurodegeneration\", \"target_gene\": \"NLRP3, CASP1, IL1B, PYCARD\", \"target_pathway\": \"Astrocyte NLRP3 inflammasome activation by alpha-synuclein aggregate-driven lysosomal disruption\", \"match_score\": 0.24, \"composite_score\": null, \"status\": \"proposed\"}, {\"id\": \"h-bdbd2120\", \"title\": \"Gamma entrainment therapy to restore hippocampal-cortical synchrony\", \"target_gene\": \"SST\", \"target_pathway\": \"GABAergic interneuron networks\", \"match_score\": 0.2, \"composite_score\": 0.6760144655243621, \"status\": \"proposed\"}, {\"id\": \"h-1e564178\", \"title\": \"Multi-Modal Stress Response Harmonization\", \"target_gene\": \"NR3C1/CRH/TNFA\", \"target_pathway\": \"Glucocorticoid receptor / stress response\", \"match_score\": 0.2, \"composite_score\": 0.5468189155920422, \"status\": \"proposed\"}, {\"id\": \"h-7f2d0e21\", \"title\": \"Peripheral-Central Immune Decoupling Therapy\", \"target_gene\": \"TREM2, complement cascade components\", \"target_pathway\": null, \"match_score\": 0.2, \"composite_score\": 0.4622222222222222, \"status\": \"proposed\"}], \"total_matching_hypotheses\": 15, \"gap_tokens_sample\": [\"IL-1alpha\", \"TNF\", \"activate\", \"amplification\", \"astrocyte\", \"astrocytes\", \"chemokines\", \"complement\", \"crosstalk\", \"il-1alpha\", \"loops\", \"microglia\", \"microglia-astrocyte\", \"neurodegeneration\", \"reactive\"], \"updated_at\": \"2026-04-06T08:21:05.727144+00:00\"}",
  "resolution_criteria": "Resolution requires: (1) In vitro or ex vivo co-culture experiments quantifying the amplification gain of the IL-1α/TNF/C1q → astrocyte activation → complement/chemokine → microglial re-activation loop, measuring ≥3 cycle iterations with cytokine concentrations and establishing a gain factor ≥2× per cycle; (2) Single-cell spatial transcriptomics of human neurodegeneration brain tissue identifying microglial and astrocyte cell states that colocalize specifically at sites of active loop amplification (≥100 cell pairs per region, ≥3 brain regions); (3) In vivo genetic interruption of ≥2 loop nodes (e.g., IL-1α plus complement or chemokine) in neurodegeneration models demonstrating synergistic reduction (≥50%) in both microglial and astrocyte activation markers, with corresponding ≥20% improvement in cognitive or neuronal survival endpoints.",
  "market_price": 0.5
}