propose

# Evaluation: ALOX15-Driven Enzymatic Ferroptosis in AD Oligodendrocytes

## Mechanistic Rationale

### Core Pathway Integration

The hypothesis presents a coherent mechanism linking neuroinflammation to oligodendrocyte death through ALOX15-mediated ferroptosis. The mechanistic chain proceeds as follows:

1. **Substrate vulnerability**: Oligodendrocytes require exceptionally high PUFA content for myelin membrane synthesis, particularly AA-PE and AdA-PE at the sn-2 position of PE
2. **Enzymatic catalysis**: ALOX15 stereospecifically oxygenates these substrates to 15-HpETE-PE and related hydroperoxides
3. **Calcium amplification**: NMDA receptor activation elevates intracellular Ca²⁺, promoting calmodulin binding to ALOX15 and enhancing catalytic activity
4. **Death execution**: PUFA-PE hydroperoxides bypass the need for iron-catalyzed initiation and directly propagate lipid peroxidation cascades

### Distinction from Microglial Ferroptosis

The proposal that this represents a distinct pathway from microglial ferroptosis is mechanistically sound. ALOX15-independent ferroptosis in microglia typically involves iron-dependent Fenton chemistry acting on free or loosely-bound PUFAs, whereas the enzymatic route specifically targets esterified PUFA pools. This compartmentalization has therapeutic implications, as ALOX15 inhibitors would selectively protect oligodendrocytes.

## Supporting Evidence Assessment

### Strong Evidence

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