The most actionable synthesis is that pathogenicity may depend more on conversion of C1q binding into classical-pathway protease activity than on C1q recognition alone. In this model, inhibiting C1r/C1s should attenuate C4/C3-mediated synapse loss and neuroinflammation while preserving some homeostatic debris sensing and cargo recognition by C1q.
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 C1QA,C1QB,C1QC,C1R,C1S,C4A,C4B,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 C1QA,C1QB,C1QC,C1R,C1S,C4A,C4B,C3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF a selective C1r/C1s inhibitor (e.g., C1s-IN-1, 10 mg/kg daily) is administered to APP/PS1 transgenic mice starting at 3 months of age for 8 weeks, THEN the density of excitatory synapses in the hip | Hippocampal PSD95+ synapse density will increase by at least 20% relative to vehicle control. | — no observation — | pending | 0.65 |
| IF human iPSC-derived neurons co-cultured with microglia are treated with a selective C1r/C1s inhibitor (C1s-IN-1, 1 µM) for 48 h prior to exposure to oligomeric Aβ (1 µM), THEN the generation of C3a | Supernatant C3a concentration will be at least 30% lower in inhibitor-treated cultures, with no significant change in C1q synaptic coverage. | — no observation — | pending | 0.55 |