Targeting microglial phosphatidylethanolamine synthesis pathway promotes GABARAP-associated phagocytosis and A clearance in Alzheimer's disease

Although metabolic activation or dysfunction of microglia is implicated in AD pathogenesis, the phospholipid metabolism–associated signaling mechanisms within microglia remain poorly defined. In this study, we demonstrate that quinolinic acid (QA), a byproduct of tryptophan catabolism via the kynurenine pathway, activates the microglial Kennedy pathway—responsible for de novo phosphatidylethanolamine (PE) biosynthesis—by upregulating the enzymes EPT1 and ETNK1.

This activation markedly enhances the synthesis of PE species enriched in polyunsaturated fatty acids. Concurrently, QA significantly increases the expression of gamma-aminobutyric acid receptor–associated protein (GABARAP), promotes its lipidation, and facilitates GABARAP-associated phagocytosis (GAP) of Aβ oligomers by microglia. Knockdown of EPT1 and ETNK1 attenuated QA-induced PE synthesis and impaired GAP of Aβ oligomers, while inhibition of GABARAP lipidation via STBD1-deconjugase substantially reduced QA-mediated GAP.