AI Summary
Key Points: - The study explores the relationship between arachidonic acid (ARA) mobilization and microglial dysfunction in Alzheimer's Disease (AD) pathology. - Lipidomic analysis of microglia from AppNL-GF mice shows increased free ARA and lysophospholipids (LPLs) and a decreased in ARA-containing phospholipids, suggesting increased ARA release from phospholipids. - Loss of lysophosphatidylcholine acyltransferase 3 (Lpcat3) in microglia reduces ARA-containing phospholipids, free ARA, and LPLs, leading to an increase in monounsaturated fatty acid-containing phospholipids, which improves oxidative stress, inflammatory responses, phagocytosis of Aβ plaques, and compaction of Aβ deposits. - The study suggests that lowering brain ARA levels through interventions may be a potential therapeutic strategy to slow down AD progression.
Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer’s disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aβ pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female AppNL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aβ plaques and promoting the compaction of Aβ deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.