Propionate\nDecreases Microglial Activation but Impairs\nPhagocytic Capacity in Response to Aggregated Fibrillar Amyloid Beta\nProtein

Microglia, the innate immune cell of the brain, are a\nprincipal\nplayer in Alzheimer’s disease (AD) pathogenesis. Their surveillance\nof the brain leads to interaction with the protein aggregates that\ndrive AD pathogenesis, most notably Amyloid Beta (Aβ). Microglia\nattempt to clear and degrade Aβ using phagocytic machinery,\nspurring damaging neuroinflammation in the process. Thus, modulation\nof the microglial response to Aβ is crucial in mitigating AD\npathophysiology. SCFAs, microbial byproducts of dietary fiber fermentation,\nare blood–brain barrier permeable molecules that have recently\nbeen shown to modulate microglial function. It is unclear whether\npropionate, one representative SCFA, has beneficial or detrimental\neffects on microglia in AD. Thus, we investigated its impact on microglial\nAβ response in vitro. Using a multiomics approach, we characterized\nthe transcriptomic, metabolomic, and lipidomic responses of immortalized\nmurine microglia following 1 h of Aβ stimulation, as well as\ncharacterizing Aβ phagocytosis and secretion of reactive nitrogen\nspecies. Propionate blunted the early inflammatory response driven\nby Aβ, downregulating the expression of many Aβ-stimulated\nimmune genes, including those regulating inflammation, the immune\ncomplement system, and chemotaxis. Further, it reduced the expression\nof <i>Apoe</i> and inflammation-promoting Aβ-binding\nscavenger receptors such as <i>Cd36</i> and <i>Msr1</i> in favor of inflammation-dampening <i>Lpl</i>, although\nthis led to impaired phagocytosis. Finally, propionate shifted microglial\nmetabolism, altering phospholipid composition and diverting arginine\nmetabolism, resulting in decreased nitric oxide production. Altogether,\nour data demonstrate a modulatory role of propionate on microglia\nthat may dampen immune activation in response to Aβ, although\nat the expense of phagocytic capacity.