Read counts for "<b>Propionate Decreases Microglial Activation but Impairs Phagocytic Capacity in response to Aggregated Fibrillar Amyloid Beta Protein</b>"

Microglia, the innate immune cell of the brain, are a principal player in Alzheimer’s Disease (AD) pathogenesis. Their surveillance of the brain leads to interaction with the protein aggregates that drive AD pathogenesis, most notably Amyloid Beta (Aβ). Microglia attempt to clear and degrade Aβ using phagocytic machinery, spurring damaging neuroinflammation in the process. Thus, modulation of the microglial response to Aβ is crucial in mitigating AD pathophysiology. SCFAs, microbial byproducts of dietary fiber fermentation, are blood-brain-barrier permeable molecules that have recently been shown to modulate microglial function. It is unclear whether propionate, one representative SCFA, has beneficial or detrimental effects on microglia in AD. Thus, we investigated its impact on microglial Aβ<b> </b>response <i>in vitro</i>. Using a multi-omics approach, we characterized the transcriptomic, metabolomic, and lipidomic responses of immortalized murine microglia following 1 hour of Aβ<b> </b>stimulation, as well as characterizing Aβ phagocytosis and secretion of reactive nitrogen species<b>. </b>Propionate blunted the early inflammatory response driven by Aβ<b>, </b>downregulating the expression of many Aβ-stimulated immune genes, including those regulating inflammation, the immune complement system, and chemotaxis. Further, it reduced the expression of <i>Apoe</i> and inflammation-promoting Aβ-binding scavenger receptors such as <i>Cd36</i> and <i>Msr1</i> in favor of inflammation-dampening <i>Lpl</i>, although this led to impaired phagocytosis. Finally, propionate shifted microglial metabolism, altering phospholipid composition and diverting arginine metabolism, resulting in decreased nitric oxide production. Altogether, our data demonstrate a modulatory role of propionate on microglia that may dampen immune activation in response to Aβ, although at the expense of phagocytic capacity.小胶质细胞（Microglia）作为大脑的固有免疫细胞，是阿尔茨海默病（AD）发病机制中的核心参与者。其对大脑的监视过程中，会与驱动AD发病的蛋白质聚集体发生相互作用，其中最具代表性的便是β淀粉样蛋白（Amyloid Beta, Aβ）。小胶质细胞会借助吞噬机制尝试清除并降解Aβ，此过程会触发破坏性的神经炎症反应。因此，调控小胶质细胞对Aβ的应答，对于缓解AD的病理生理进程至关重要。 短链脂肪酸（short-chain fatty acids, SCFAs）是膳食纤维发酵产生的微生物代谢副产物，属于可穿透血脑屏障（blood-brain barrier）的分子，近期研究证实其能够调控小胶质细胞功能。目前尚不明确丙酸（propionate）作为典型SCFAs之一，对AD状态下的小胶质细胞究竟发挥有益还是有害的作用。为此，本研究探究了其对小胶质细胞Aβ应答的体外（in vitro）影响。 本研究采用多组学研究策略，对经Aβ刺激1小时后的永生化小鼠小胶质细胞的转录组、代谢组及脂质组应答特征进行了系统表征，同时分析了Aβ吞噬作用与活性氮物种（reactive nitrogen species）的分泌情况。 结果显示，丙酸可抑制Aβ诱导的早期炎症应答，下调多种Aβ刺激后上调的免疫基因的表达，其中涵盖调控炎症、免疫补体系统及趋化作用的相关基因。此外，丙酸还下调了载脂蛋白E（Apoe）以及促进炎症的Aβ结合清道夫受体（如Cd36、Msr1）的表达，转而上调具有抗炎作用的Lpl，但该变化会导致小胶质细胞的吞噬能力受损。最后，丙酸可重塑小胶质细胞的代谢模式，改变磷脂组成并分流精氨酸代谢通路，最终使一氧化氮生成量显著降低。 综上，本研究数据表明丙酸对小胶质细胞具有调控作用，能够抑制小胶质细胞针对Aβ的免疫激活，但这一效应是以牺牲吞噬能力为代价的。