Resolve: TREM2 Deficiency Drives Microglial Senescence via Lipid Metabolism Dysregulation

Challenge generated from hypothesis h-0ca0f0f8f2 (composite_score=0.800). Target gene/pathway: TREM2/TYROBP. Source hypothesis: TREM2 Deficiency Drives Microglial Senescence via Lipid Metabolism Dysregulation. ## Falsifiable Predictions 1. TREM2-KO primary microglia show >2-fold elevation in p21/p16 senescence markers and >1.5-fold increase in SASP cytokines (IL-6, IL-1β) vs WT at 14 DIV. 2. TREM2-KO microglia accumulate cholesterol esters >3-fold vs WT (lipidomics by LC-MS/MS) and show impaired cholesterol efflux (>40% reduction in ABCA1 transport assay). 3. LXR agonist (GW3965) treatment restores cholesterol efflux to WT levels and reduces p21 by >40% in TREM2-KO microglia. 4. Navitoclax senolytic clears >50% of p21-high microglia in TREM2-KO mice and reduces neuroinflammatory gene signature (NanoString nCounter) by >35%.

$500

OPEN

Confidence:

50%

Created: 2026-04-27

Linked Targets (2)

ABCA1 ATP-binding cassette transporter A1 PDB:7QS70.56

🧬 View 3D Structure — PDB 7QS7 click to expand

TREM2 Triggering receptor expressed on myeloid cells 2 PDB:5UD70.63

🧬 View 3D Structure — PDB 5UD7 click to expand

Detected Targets:

TREM2 ABCA1

3D Protein Structure

▶ View 3D structure: TREM2 — PDB 6YXY

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

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Linked Hypotheses (1)

TREM2 Deficiency Drives Microglial Senescence via Lipid Metabolism Dysregulation TREM2/TYROBP0.84