Circulating hs-CRP as Disease-Modifying Target via Microglial IL-1β Amplification
Curated pathway from expert analysis
flowchart TD
A["Circulating hs-CRP Elevation<br/>Systemic Inflammatory Signal"]
B["Microglial Fc/TLR4 Priming<br/>MyD88/NFkB Tone Increased"]
C["pro-IL1B Production<br/>Inflammasome Substrate Accumulates"]
D["NLRP3-Caspase-1 Cleavage<br/>Mature IL-1beta Release"]
E["Feed-Forward Neuroinflammation<br/>Synaptic Stress and Neuronal Injury"]
F["CRP Lowering or IL1B Blockade<br/>Inflammatory Amplifier Interrupted"]
A --> B
B --> C
C --> D
D --> E
F -.->|"blunts"| D
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CRP yet. Search RCSB →
Median TPM across 13 brain regions for CRP → IL-1β → TLR4/MyD88 axis 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 CRP → IL-1β → TLR4.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we stratify postmortem Alzheimer's disease brains from the Accelerating Medicines Partnership Alzheimer's Disease cohort into high hs-CRP (pre-mortem serum >10 mg/L, n≥40) versus low hs-CRP (pre-mo | High hs-CRP group will show ≥2-fold higher TLR4/MyD88 mRNA expression and ≥50% higher IL-1β protein in Iba1+ microglia relative to low hs-CRP group. | — no observation — | pending | 0.65 |
| IF we administer a monoclonal antibody targeting CRP (e.g., CRPH001 or similar) to reduce circulating hs-CRP by ≥70% for 6 months in adults with elevated hs-CRP (>3 mg/L) and early Alzheimer's disease | CSF IL-1β concentration will decrease by ≥40% and CDR-SB progression will be reduced by ≥30% in the CRP-lowered treatment arm versus placebo at 6-month follow-u | — no observation — | pending | 0.55 |