ω-3 Docosahexaenoic Acid (DHA) Metabolism via 15-Lipoxygenase to Generate Speci…

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). The hypothesis predicts that enhanced 15-LOX expression or activity in brain tissue will correlate with increased SPM levels and reduced neuroinflammatory markers in both transgenic Alzheimer’s mouse models and human post-mortem brain samples. Therapeutic intervention could involve 15-LOX pathway activation through dietary DHA supplementation, direct SPM administration, or pharmacological enhancement of endogenous SPM biosynthesis. This approach shifts from preventing Aβ-induced membrane damage to actively resolving the chronic neuroinflammation that perpetuates neurodegeneration, offering a complementary therapeutic angle that addresses the inflammatory cascade downstream of initial Aβ pathology.