Description
What are the mechanisms by which tau pathology spreads through connected brain regions via prion-like transmission, trans-synaptic transfer, and extracellular vesicles? What are the key interception points for therapeutic intervention at each propagation step?
Resolution criteria
Resolved when: a curated evidence synthesis separates tau propagation routes, affected connected brain regions, molecular carriers, and intervention points, supported by at least two experimental systems or human network/pathology studies. SciDEX must add KG edges for propagation mechanism, region, carrier, and therapeutic target, and produce a debate or scored hypothesis ranking the most actionable interception points.
Evidence summary
{“hypothesis_matches”: [{“id”: “h-var-3b982ec3d2”, “title”: “Closed-loop tACS targeting entorhinal cortex layer II SST interneurons to block tau propagation and restore perforant-path gamma gating in Alzheimer’s disease”, “target_gene”: “SST”, “target_pathway”: “Entorhinal cortex layer II SST interneuron-mediated perforant-path gamma gating and suppression of trans-synaptic tau propagation to hippocampus”, “match_score”: 0.37, “composite_score”: null, “status”: “proposed”}, {“id”: “h-var-55da4f915d”, “title”: “Closed-loop transcranial focused ultrasound targeting entorhinal cortex layer II SST interneurons to restore perforant-path gamma gating and block tau propagation in Alzheimer’s disease”, “target_gene”: “SST”, “target_pathway”: “Entorhinal cortex layer II SST interneuron mechanosensitive activation via tFUS-driven PIEZO1/TREK-1 signaling, restoration of perforant-path gamma gating, and suppression of trans-synaptic tau propagation to hippocampus”, “match_score”: 0.37, “composite_score”: null, “status”: “proposed”}, {“id”: “h-a87702b6”, “title”: “Cholesterol-CRISPR Convergence Therapy for Neurodegeneration”, “target_gene”: “HMGCR, LDLR, APOE regulatory regions”, “target_pathway”: “Brain cholesterol homeostasis (HMGCR synthesis \u2192 CYP46A1 elimination)”, “match_score”: 0.3, “composite_score”: 0.5150203412333288, “status”: “proposed”}, {“id”: “h-29ef94d5”, “title”: “Epigenetic Memory Reprogramming for Alzheimer’s Disease”, “target_gene”: “BDNF, CREB1, synaptic plasticity genes”, “target_pathway”: “CREB/BDNF epigenetic regulation of synaptic plasticity”, “match_score”: 0.3, “composite_score”: 0.49103059326293774, “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”: 0.3, “composite_score”: null, “status”: “proposed”}, {“id”: “h-d78123d1”, “title”: “Microglia-Derived Extracellular Vesicle Engineering for Targeted Mitochondrial Delivery”, “target_gene”: “RAB27A/LAMP2B”, “target_pathway”: “Extracellular vesicle biogenesis (ESCRT/Rab27a) / mitochondrial transfer”, “match_score”: 0.27, “composite_score”: 0.3681729702065991, “status”: “proposed”}, {“id”: “h-fdaae8d9”, “title”: “Trans-Synaptic Adhesion Molecule Modulation”, “target_gene”: “NLGN1”, “target_pathway”: “Synaptic function / plasticity”, “match_score”: 0.24, “composite_score”: 0.33763444613187854, “status”: “proposed”}, {“id”: “h-3a4f2027”, “title”: “Trinucleotide Repeat Sequestration via CRISPR-Guided RNA Targeting”, “target_gene”: “HTT, DMPK, repeat-containing transcripts”, “target_pathway”: “CRISPR-Cas13 RNA targeting / trinucleotide repeat expansion”, “match_score”: 0.2, “composite_score”: 0.515020341233329, “status”: “proposed”}, {“id”: “h-9d22b570”, “title”: “Programmable Neuronal Circuit Repair via Epigenetic CRISPR”, “target_gene”: “NURR1, PITX3, neuronal identity transcription factors”, “target_pathway”: “CRISPRa epigenetic activation of dopaminergic transcription factor network”, “match_score”: 0.2, “composite_score”: 0.4470493886505538, “status”: “proposed”}, {“id”: “h-seaad-7f15df4c”, “title”: “Excitatory Neuron Vulnerability via SLC17A7 Downregulation”, “target_gene”: “SLC17A7”, “target_pathway”: “Glutamatergic Transmission / Synaptic Function”, “match_score”: 0.2, “composite_score”: 0.4465701905133076, “status”: “proposed”}], “total_matching_hypotheses”: 11, “gap_tokens_sample”: [“brain”, “connected”, “extracellular”, “interception”, “intervention”, “pathology”, “points”, “prion”, “prion-like”, “propagation”, “regions”, “spreads”, “synaptic”, “trans”, “trans-synaptic”], “updated_at”: “2026-04-06T08:21:05.790624+00:00”}