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.