ALOX15 (Arachidonate 15-Lipoxygenase) is an enzyme that catalyzes the oxidation of polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid, to produce bioactive lipid mediators. It plays important roles in inflammation, immune regulation, and has been increasingly implicated in neurodegenerative processes including Alzheimer's Disease and Parkinson's Disease.
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¶ Domain Architecture
- N-terminal PLAT domain (Polycystin-1, Lipoxygenase, Alpha-toxin): ~100 aa, membrane association
- Catalytic lipoxygenase domain: ~450 aa, contains the iron-containing active site
- C-terminal regulatory region: Contains residues that modulate enzyme activity
- Iron-binding motif: His-X4-His-X17-His-X4-His
- Substrate binding pocket: Hydrophobic channel for fatty acid entry
- Phospholipid binding interface in PLAT domain
ALOX15 produces various bioactive lipid mediators through peroxidation of polyunsaturated fatty acids:
- 15(S)-HETE (15(S)-Hydroxyeicosatetraenoic acid): Major product from arachidonic acid
- 13(S)-HODE (13(S)-Hydroxyoctadecadienoic acid): Major product from linoleic acid
- Lipoxins: Anti-inflammatory mediators (via transcellular biosynthesis)
- ** resolvins**: Specialized pro-resolving mediators
| Activity |
Description |
| Inflammation Resolution |
Key enzyme in SPM biosynthesis, promotes resolution |
| Cell Signaling |
Modulates NF-κB, MAPK pathways |
| Membrane Remodeling |
Phospholipid remodeling and ferroptosis regulation |
| Immune Regulation |
T-cell differentiation, macrophage polarization |
ALOX15 is significantly elevated in AD brain tissue, particularly in regions surrounding amyloid plaques:
- Plaque Association: 15-LOX colocalizes with amyloid plaques in AD hippocampus and cortex
- Neuroinflammation: Promotes production of pro-inflammatory cytokines (IL-1β, TNF-α)
- APP Processing: Enhances amyloidogenic APP processing via BACE1 upregulation
- Tau Pathology: Associated with tau phosphorylation and aggregation
- Lipid Peroxidation: Increases 4-HNE production, contributing to oxidative damage
Elevated 15-LOX activity observed in PD substantia nigra and striatum:
- Dopaminergic Toxicity: 15-HETE promotes dopaminergic neuron death
- α-Synuclein Aggregation: Lipid peroxidation products accelerate α-synuclein oligomerization
- Mitochondrial Dysfunction: Impairs complex I activity
- Neuroinflammation: Activates microglia in substantia nigra
- Elevated ALOX15 in motor cortex and spinal cord of ALS patients
- Contributes to motor neuron death through lipid peroxidation
- Implicated in SOD1 aggregation pathology
ALOX15 is a key regulator of ferroptosis, an iron-dependent form of cell death:
- Generates lipid peroxides that execute ferroptosis
- 15-LOX inhibitors (e.g., baicalein, PD146176) block ferroptosis
- Potential therapeutic target for neurodegenerative diseases
| Compound |
Mechanism |
Development Stage |
| Baicalein |
Direct 15-LOX inhibition |
Preclinical |
| PD146176 |
Selective 15-LOX inhibition |
Preclinical |
| Revalip |
15-LOX/12-LOX dual inhibitor |
Research |
| CDC |
15-LOX inhibitor |
Research |
- Neuroprotection: 15-LOX inhibitors protect neurons from oxidative damage
- Anti-inflammatory: Reduce neuroinflammation in AD/PD models
- Anti-aggregation: Prevent protein aggregation via lipid peroxidation reduction
- Ferroptosis Blockade: Inhibit ferroptotic cell death
- Blood-brain barrier penetration is a challenge for 15-LOX inhibitors
- Enzyme redundancy (multiple lipoxygenases) may limit efficacy
- Timing of intervention likely critical (early vs. late disease)
- ALOX15 gene located on chromosome 17p13.2
- Single nucleotide polymorphisms (SNPs) associated with:
- Cardiovascular disease risk
- Asthma susceptibility
- Potential links to neurodegeneration (under investigation)
- No strong causal variants identified for AD/PD to date
- 15-HETE levels in CSF: Potential biomarker for neuroinflammation
- 13-HODE: Elevated in AD plasma
- May serve as pharmacodynamic marker for 15-LOX inhibitor trials