TREM2 R47H and ABI3 rs616338 are both AD risk loci linked to microglial response, phagocytosis, and cytoskeletal remodeling. The notebook prioritizes them as a convergent module rather than isolated targets. Hypothesis: restoring TREM2-dependent lipid sensing together with ABI3-linked actin remodeling will rescue plaque engagement and debris clearance more robustly than modulating either locus alone in human iPSC-microglia.
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Curated Mechanism Pathway
Curated pathway diagram from expert analysis
flowchart TD
A["Amyloid-beta Plaques Phospholipid Ligands"]
B["TREM2 Receptor Ligand Binding"]
C["TYROBP/DAP12 ITAM Phosphorylation"]
D["SYK Kinase Activation"]
E["PLCG2 IP3 + DAG Generation"]
F["Ca2+ Release Cytoskeletal Remodeling"]
G["Microglial Phagocytosis Plaque Compaction"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784
Dimension Scores
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8 citations5 with PMIDValidation: 0%7 supporting / 1 opposing
✓For(7)
No supporting evidence
No opposing evidence
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Evidence Matrix — sortable by strength/year, click Abstract to expand
Evidence Types
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PMIDs
Abstract
TREM2 R47H has a high AD risk odds-ratio proxy and…
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GENE
dataset:ad_gene…
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Enrichment and druggability scoring group TREM2 an…
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GENE
notebook:gwas-a…
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Rare coding variants in PLCG2, ABI3, and TREM2 imp…
Joint modulation could be context-dependent and may not translate from iPSC-microglia to aged human brain micr…▼
Joint modulation could be context-dependent and may not translate from iPSC-microglia to aged human brain microglia.
notebook:gwas-ad-risk-loci-analysis
Multi-persona evaluation:
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IF human iPSC-derived microglia from AD patients harboring both TREM2 R47H and ABI3 rs616338 risk alleles receive AAV-mediated combinatorial overexpression of TREM2 and ABI3 THEN plaque-associated microglial coverage and amyloid-beta debris clearance will increase by ≥40% compared to single-locus interventions (TREM2-only or ABI3-only) within 8 weeks post-treatment.
pendingconf: 0.65
Expected outcome: Combinatorial TREM2+ABI3 overexpression will yield ≥40% greater phagocytic index (amyloid-beta internalization + degradation) and ≥35% increase in plaque-engaged microglia versus either single-locus treatment, with significance at p<0.01 by two-way ANOVA.
Falsified by: If combinatorial treatment produces ≤15% improvement in phagocytic index compared to the superior single-locus condition, the convergent-module hypothesis is falsified and independent locus effects will be inferred.
Method: iPSC-microglia differentiated from AD patients carrying both TREM2 R47H and ABI3 rs616338 risk variants (n≥4 lines); AAV9-mediated overexpression constructs; 10x chromium amyloid-beta opsonized beads or human AD brain slice co-culture; live-cell confocal imaging and flow cytometry phagocytosis assay at 4 and 8 weeks.
IF TREM2-ABI3 double knockout iPSC-microglia receive rescue with TREM2+ABI3 co-expression THEN actin polymerization rates (F-actin/G-actin ratio) and podosome/phagocytic cup dynamics will show ≥50% restoration toward WT levels and exceed single-gene rescue by ≥30% within 6 weeks.
pendingconf: 0.55
Expected outcome: F-actin/G-actin ratio measured by G-actin/F-actin in vivo assay will increase ≥50% in dual-rescue vs double KO, and ≥30% higher than TREM2-only rescue; phagocytic cup closure time will decrease by ≥40% versus double KO.
Falsified by: If dual rescue shows ≤20% improvement in F-actin dynamics over single-gene rescue, or actin polymerization remains <30% of WT levels, the synergistic actin-phagocytosis coupling model is falsified.
Method: CRISPR-generated TREM2-ABI3 double KO iPSC line and isogenic WT control; lentiviral co-expression or bacterial artificial chromosome rescue vectors; LifeAct-GFP live imaging of actin dynamics; F-actin/G-actin fractionation assay (n≥3 replicates per condition); automated high-content analysis.