Friday Cassi M, Stephens Isaiah O, Smith Cathryn T, Lee Sangderk, Satish Diksha, Devanney Nicholas A, Cohen Sarah, Morganti Josh M, Gordon Scott M, Johnson Lance A
Department of Physiology, University of Kentucky, Lexington, KY, USA.
Department of Physiology, University of Kentucky, Lexington, KY, USA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Neurobiol Dis. 2025 Aug;212:106983. doi: 10.1016/j.nbd.2025.106983. Epub 2025 May 30.
Excess lipid droplet (LD) accumulation is implicated in various diseases, including Alzheimer's disease (AD), yet the mechanisms underlying this accumulation remain unclear. Apolipoprotein E (ApoE) is a droplet-associated protein, and its E4 variant confers the greatest genetic risk for late-onset AD while also being linked to increased neuroinflammation and LD accumulation. In this study, we compared the lipid and protein composition of hepatic LDs in targeted replacement mice expressing human E3 (neutral) or E4 (risk variant), under both baseline conditions and following lipopolysaccharide (LPS) administration. Lipidomic analysis revealed that E4 LDs exhibit a shift in glycerophospholipid distribution, with an increase in phosphatidylcholine species, such that their baseline profile resembles that of LPS-treated LDs. Quantitative proteomics indicated that E4 LDs are enriched in proteins related to vesicle transport but show decreased levels of proteins involved in fatty acid β-oxidation. Notably, many LD-associated proteins overlapped with those identified in AD postmortem and microglial 'omics studies, suggesting a role for LDs in AD pathogenesis. To further explore these findings, primary microglia from E3 and E4 mice were exposed to exogenous lipids, LPS, and necroptotic N2A cells. Under most conditions, E4 microglia accumulated more LDs and secreted higher levels of proinflammatory cytokines (TNF, IL-1β, IL-10) compared to E3 microglia, although their LPS response was blunted. These data suggest that altered LD dynamics in E4 microglia may contribute to the increased AD risk associated with APOE4.
过量的脂滴（LD）积累与包括阿尔茨海默病（AD）在内的多种疾病有关，但其积累背后的机制仍不清楚。载脂蛋白E（ApoE）是一种与脂滴相关的蛋白质，其E4变体赋予晚发性AD最大的遗传风险，同时也与神经炎症增加和LD积累有关。在本研究中，我们比较了在基线条件下和给予脂多糖（LPS）后，表达人类E3（中性）或E4（风险变体）的靶向替代小鼠肝脏LD的脂质和蛋白质组成。脂质组学分析显示，E4脂滴的甘油磷脂分布发生变化，磷脂酰胆碱种类增加，因此其基线特征类似于LPS处理后的脂滴。定量蛋白质组学表明，E4脂滴富含与囊泡运输相关的蛋白质，但参与脂肪酸β氧化的蛋白质水平降低。值得注意的是，许多与脂滴相关的蛋白质与AD死后和小胶质细胞“组学”研究中鉴定的蛋白质重叠，表明脂滴在AD发病机制中起作用。为了进一步探索这些发现，将来自E3和E4小鼠的原代小胶质细胞暴露于外源性脂质、LPS和坏死性N2A细胞。在大多数情况下，与E3小胶质细胞相比，E4小胶质细胞积累了更多的脂滴，并分泌了更高水平的促炎细胞因子（TNF、IL-1β、IL-10），尽管它们对LPS的反应减弱。这些数据表明，E4小胶质细胞中脂滴动态的改变可能导致与APOE4相关的AD风险增加。
