ω-3 Docosahexaenoic Acid (DHA) Metabolism via 15-Lipoxygenase to Generate Specialized Pro-Resolving Mediators Against Neuroinflammation in Alzheimer's Disease
🧪 Overview
This hypothesis proposes that 15-lipoxygenase (15-LOX) enzymatically converts docosahexaenoic acid (DHA) into specialized pro-resolving mediators (SPMs), specifically resolvin D1 (RvD1) and protectin D1 (PD1), to combat neuroinflammation in Alzheimer's disease rather than focusing on membrane rigidification. The mechanism centers on 15-LOX's ability to perform stereoselective oxygenation of DHA at the 17S position, initiating a biosynthetic cascade that produces these potent anti-inflammatory and pro-resolution lipid mediators. Unlike the parent hypothesis targeting membrane protection, this variant addresses the inflammatory component of Alzheimer's pathogenesis through active resolution of neuroinflammation. RvD1 and PD1 function by binding to specific G-protein coupled receptors (GPR32, ALX/FPR2) on microglia and astrocytes, triggering signaling cascades that promote efferocytosis of apoptotic neurons, reduce pro-inflammatory cytokine production (TNF-α, IL-1β), and enhance neuroprotective factor release (BDNF, NGF).
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["DHA Substrate Pool<br/>Membrane Omega-3 Lipids"]
B["CYP2J2 Epoxygenase<br/>DHA-to-Epoxide Conversion"]
C["Epoxy-DHA Mediators<br/>Anti-inflammatory Lipid Signals"]
D["sEH Inhibition<br/>Epoxide Lifetime Prolonged"]
E["Synaptic Membrane Fluidity<br/>A-beta-Induced Rigidification Blocked"]
F["Excitatory Signaling Stability<br/>Receptor Mobility Preserved"]
G["Synaptic Protection<br/>Reduced A-beta Toxicity"]
A --> B
B --> C
D --> C
C --> E
E --> F
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — ALOX15
No curated PDB or AlphaFold mapping for ALOX15 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for ALOX15/15-LOX from GTEx v10.
💉 Clinical Trials
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 ALOX15.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |