RT Journal Article
SR Electronic
T1 Arachidonic Acid Mobilization and Peroxidation Promote Microglial Dysfunction in Aβ Pathology
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP e0202242024
DO 10.1523/JNEUROSCI.0202-24.2024
VO 44
IS 31
A1 Lin, Da
A1 Gold, Andrew
A1 Kaye, Sarah
A1 Atkinson, Jeffrey R.
A1 Tol, Marcus
A1 Sas, Andrew
A1 Segal, Benjamin
A1 Tontonoz, Peter
A1 Zhu, Jiangjiang
A1 Gao, Jie
YR 2024
UL http://www.jneurosci.org/content/44/31/e0202242024.abstract
AB 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.