Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
Department of Human Sciences, The Ohio State University, Columbus, Ohio 43210.
J Neurosci. 2024 Jul 31;44(31):e0202242024. doi: 10.1523/JNEUROSCI.0202-24.2024.
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 App 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 (), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial 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 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.
花生四烯酸（ARA）的异常增加长期以来一直与阿尔茨海默病（AD）的病理学有关，但其潜在的因果机制尚不清楚。在这项研究中，我们揭示了 Aβ病理学中 ARA 动员与小胶质细胞功能障碍之间的联系。来自 App 小鼠的原代小胶质细胞的脂质组学分析显示，游离 ARA 和溶血磷脂（LPL）显著增加，而含有 ARA 的磷脂（PL）减少，提示 PL 中 ARA 释放增加。为了操纵小胶质细胞中的 ARA 含 PL，我们通过基因敲除了溶血磷脂酰胆碱酰基转移酶 3（），这是主要的酶，催化 ARA 掺入 PL。小胶质细胞缺失减少了 ARA 含 PL、游离 ARA 和 LPL 的水平，导致雄性和雌性 小鼠中 MUFA 含 PL 的代偿性增加。值得注意的是，小胶质细胞中 ARA 的减少显著改善了氧化应激和炎症反应，同时增强了 Aβ斑块的吞噬作用，并促进了 Aβ沉积的致密化。从机制上讲，scRNA seq 表明，LPCAT3 缺乏通过促进从头脂质合成来促进吞噬作用，同时保护小胶质细胞免受氧化损伤。总的来说，我们的研究揭示了 AD 中小胶质细胞中 ARA 动员和功能障碍之间的新的机制联系。通过药理学或饮食干预降低大脑中的 ARA 水平可能是减缓 AD 进展的一种潜在治疗策略。
