ID: hyp-sda-2026-04-01-001-6
Hypothesis
Soluble TREM2 Sequestration and Recycling
Engineered proteins to capture shed soluble TREM2 and facilitate membrane re-insertion or prevent proteolytic cleavage.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
Engineered proteins to capture shed soluble TREM2 and facilitate membrane re-insertion or prevent proteolytic cleavage
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Surface TREM2 on Microglia<br/>Phagocytic Receptor"]
B["ADAM10 and ADAM17 Shedding<br/>Ectodomain Proteolytic Cleavage"]
C["Soluble TREM2 Released to CSF<br/>Non-Signaling Truncated Fragment"]
D["Microglial Surface TREM2 Depleted<br/>Reduced Phagocytic Signaling"]
E["Engineered Capture Proteins<br/>High Affinity sTREM2 Binding"]
F["Membrane Re-Insertion Facilitated<br/>or ADAM Shedding Prevented"]
G["Surface TREM2 Restored<br/>TYROBP-SYK Signaling Recovered"]
H["Microglial Phagocytic Capacity<br/>Amyloid Clearance Restored"]
A --> B
B --> C
B --> D
D -.->|"insufficient signaling"| H
C --> E
E --> F
F --> G
G --> H
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53.
Supports
TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.
Supports
TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy.
Supports
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — ['TREM2']
No curated PDB or AlphaFold mapping for ['TREM2'] yet. Search RCSB →
💉 Clinical Trials (5)
0
Active
Active
0
Completed
Completed
0
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
UNKNOWN·NCT05419596 · Istanbul University
Cognitive Dysfunction
Urologic Surgery
COMPLETED·NCT06224920 · Ludwig-Maximilians - University of Munich
Alzheimer Disease Corticobasal Syndrome
magnetic resonance imaging electroencephalography blood and CSF biomarker
RECRUITING·NCT06274528 · Washington University School of Medicine
Alzheimer Disease
Lemborexant 10 mg Lemborexant 20mg Placebo
COMPLETED·NCT04388254 · Cassava Sciences, Inc.
Alzheimer Disease
Simufilam 100 mg oral tablet Placebo
COMPLETED·NCT04570644 · AZTherapies, Inc.
Healthy Volunteers Alzheimer Disease
ALZT-OP1 (cromolyn and ibuprofen) ALZT-OP1a (cromolyn) and ALZT-OP1b (ibuprofen)
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 ['TREM2'].
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
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📊 Market Indicators
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF engineered proteins designed to sterically block TREM2 cleavage sites (mutant TREM2-Fc with substrate-mimicking linker) are co-expressed with wild-type TREM2 in HEK293 cells THEN proteolytic cleava | Significantly reduced intensity of ~20 kDa sTREM2 band in conditioned media Western blot; sTREM2 concentration <40% of control levels by ELISA | — no observation — | pending | 0.70 |
| IF engineered TREM2-sequestration proteins (e.g., TREM2-Fc fusion with membrane-targeting domain) are applied to TREM2-expressing microglial cell cultures THEN membrane-associated TREM2 levels will in | Increased surface TREM2 immunofluorescence intensity and Western blot signal from surface-biotinylated fractions; reduced sTREM2 concentration in media measured | — no observation — | pending | 0.75 |
🔮 Falsifiable Predictions (2)
pendingconf 75%
IF engineered TREM2-sequestration proteins (e.g., TREM2-Fc fusion with membrane-targeting domain) are applied to TREM2-expressing microglial cell cultures THEN membrane-associated TREM2 levels will increase by ≥50% (measured by surface biotinylation assay and flow cytometry) while soluble TREM2 in c
Predicted outcome: Increased surface TREM2 immunofluorescence intensity and Western blot signal from surface-biotinylated fractions; reduced sTREM2 concentration in medi
Falsification: No significant change in membrane TREM2 levels OR no reduction in soluble TREM2 concentration indicates the engineered protein fails to capture and re-insert soluble TREM2, disproving the hypothesis
pendingconf 70%
IF engineered proteins designed to sterically block TREM2 cleavage sites (mutant TREM2-Fc with substrate-mimicking linker) are co-expressed with wild-type TREM2 in HEK293 cells THEN proteolytic cleavage of TREM2 will be reduced by ≥60% (measured by reduced sTREM2 fragment in media via Western blot a
Predicted outcome: Significantly reduced intensity of ~20 kDa sTREM2 band in conditioned media Western blot; sTREM2 concentration <40% of control levels by ELISA
Falsification: Equivalent or increased sTREM2 fragment generation in co-expression condition compared to TREM2-only control indicates the engineered protein cannot prevent proteolytic cleavage, disproving this aspec
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _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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