This hypothesis reconciles conflicting C1q phenotypes by placing receiver-cell state downstream of a common upstream C1q-tagging event. In a competent TREM2 program, microglia clear tagged material efficiently; in TREM2-impaired states, the same substrates persist, amplifying complement and bystander synapse loss.
Curated pathway from expert analysis
flowchart TD
A["C1Q Deficiency<br/>Impaired Clearance of Apoptotic Cells"]
B["C1QC Assembly<br/>Heterocomplex Formation"]
C["Synaptic Pruning Dysregulation<br/>Unpruned Connections"]
D["Microglial Overactivation<br/>Complement Deposition"]
E["C3b/C4b Deposition<br/>Neuronal Surface"]
F["Synaptic Loss<br/>Excessive Pruning in AD"]
G["Long-Term Potentiation<br/>Memory Formation Impaired"]
H["Cognitive Decline<br/>AD-Related Dementia"]
A --> B
B --> C
B --> D
C --> F
D --> E
E --> F
F --> G
G --> H
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for TREM2,TYROBP,C1QA,C1QB,C1QC,C3 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
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,TYROBP,C1QA,C1QB,C1QC,C3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF TREM2 signaling is activated pharmacologically (using agonistic antibody clone 5F12 at 10 mg/kg, i.p., 3x/week for 4 weeks) in 12-month-old TREM2-WT mice with established C1q-bound synaptic debris, | ≥40% increase in microglial engulfment of C1q-tagged synaptic elements, quantified as Iba1+ cells containing ≥3 C1q+Synapsin+ puncta | — no observation — | pending | 0.65 |
| IF TREM2 is genetically ablated (TREM2-KO) in 5xFAD amyloid model mice, THEN cortical synaptosomal C3 protein levels will increase by ≥2.5-fold at 6 months of age compared to TREM2-WT 5xFAD controls, | ≥2.5-fold increase in C3 concentration (ng/mg synaptosomal protein) and ≥1.8-fold increase in C1q subunits in TREM2-KO vs. TREM2-WT 5xFAD mice | — no observation — | pending | 0.55 |