This hypothesis proposes that CYP2J2-generated DHA epoxides act as endogenous LXRβ agonists, creating a synergistic mechanism for synaptic protection against Alzheimer's disease pathology. DHA epoxides produced by CYP2J2 metabolism serve a dual function: directly protecting synaptic membranes from Aβ-induced rigidification through membrane incorporation, while simultaneously activating LXRβ signaling to enhance APOE lipidation and cholesterol efflux. This creates a positive feedback loop where DHA epoxide generation promotes both membrane fluidity maintenance and improved lipid transport capacity. LXRβ activation by DHA epoxides upregulates ABCA1 expression, facilitating cholesterol transfer to APOE and generating properly lipidated APOE particles that can more effectively clear Aβ aggregates. Concurrently, the DHA epoxides integrate into synaptic membranes, counteracting cholesterol-mediated membrane rigidification and preserving optimal membrane dynamics for synaptic function. The hypothesis predicts that CYP2J2 upregulation or sEH inhibition will amplify this protective circuit by increasing DHA epoxide availability.

This hypothesis proposes that CYP2J2-generated DHA epoxides act as endogenous LXRβ agonists, creating a synergistic mechanism for synaptic protection against Alzheimer's disease pathology. DHA epoxides produced by CYP2J2 metabolism serve a dual function: directly protecting synaptic membranes from Aβ-induced rigidification through membrane incorporation, while simultaneously activating LXRβ signaling to enhance APOE lipidation and cholesterol efflux. This creates a positive feedback loop where DHA epoxide generation promotes both membrane fluidity maintenance and improved lipid transport capacity. LXRβ activation by DHA epoxides upregulates ABCA1 expression, facilitating cholesterol transfer to APOE and generating properly lipidated APOE particles that can more effectively clear Aβ aggregates. Concurrently, the DHA epoxides integrate into synaptic membranes, counteracting cholesterol-mediated membrane rigidification and preserving optimal membrane dynamics for synaptic function. The hypothesis predicts that CYP2J2 upregulation or sEH inhibition will amplify this protective circuit by increasing DHA epoxide availability. This mechanism explains why DHA supplementation shows variable cognitive benefits – efficacy depends on adequate CYP2J2 expression and functional LXRβ signaling. The model suggests that individuals with genetic variants affecting CYP2J2 activity or LXRβ function may show differential responses to omega-3 interventions, and that combination therapies targeting both pathways could provide superior neuroprotection compared to single-target approaches.