Ffar4 mediated regulation of inflammation in Alzheimer’s disease

Neuroinflammation is a hallmark of Alzheimer’s disease (AD), with microglia playing a central role in AD pathogenesis. The objective of this study is to identify a novel therapeutic target to regulate inflammation in the context of AD. Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor for medium and long-chain fatty acids, including, but not limited to, omega-3-polyunsaturated fatty acids (FAs). Ffar4 is expressed in a variety of tissues, including microglia. Ffar4 has been shown to attenuate inflammation, reduce oxidative stress, and prevent apoptosis in many tissues. Additionally, Ffar4 signaling produces FA metabolites, or oxylipins, that confer anti-inflammatory and pro-resolving cellular effects. We hypothesize that targeting Ffar4 signaling will preserve a more anti-inflammatory/pro-resolving environment and potentially improve cognitive function. To test this hypothesis, we applied several approaches to evaluate the impact of Ffar4 on neuroinflammation. To determine the impact of activating Ffar4 in the context of inflammation, mice were treated with the Ffar4 agonist, TUG-891, and then challenged with lipopolysaccharide (LPS) to induce an inflammatory response. Furthermore, the macrophage cell line, RAW264.7, was treated with TUG-891 and subjected to LC/MS/MS to detect the production of pro- and anti-inflammatory oxylipins. For in vivo studies APPSAA knock-in (KI) mice (Jackson, strain #034711) were used to model AD. Brain regions from wild-type (WT), APPSAA KI, Ffar4 knockout (KO), and APPSAA KI/Ffar4KO mice underwent LC/MS/MS analysis to detect the presence of pro- and anti-inflammatory oxylipins. Our data indicate that activation of Ffar4 significantly reduces the level of pro-inflammatory cytokines in the brains of animals treated with LPS. This indicates that Ffar4 may be effective at attenuating neuroinflammation. Treatment of the macrophage cell line, RAW264.7, with TUG-891 resulted in enhanced anti-inflammatory oxylipin production. Additionally, we observed pronounced alterations in the oxylipin content of brain tissues. APPSAA KI mice exhibited an increase in pro-inflammatory oxylipins compared to WT animals. Loss of Ffar4 further exacerbated the production of pro-inflammatory oxylipins, while also reducing the production of anti-inflammatory oxylipins. These data indicate that Ffar4 can mediate neuroinflammation by regulating production of inflammatory cytokines in addition to pro- and anti-inflammatory oxylipins. Perturbations in brain oxylipin content has been demonstrated in the brains of AD patients compared to health controls, with more pro-inflammatory oxylipins present in the brains of AD patients. Our data reveal similar changes in oxylipin content in a mouse model of AD and these changes are exacerbated by loss of Ffar4. These data indicate that Ffar4 can modulate the inflammatory tissue environment. Given that Ffar4 attenuates inflammation, activating Ffar4 could mitigate AD-related neuroinflammation. These results suggest that Ffar4 may be a therapeutic target for regulating neuroinflammation in the context of AD. This work was supported by NIH R03AG078686 (KAM), NIH R01HL152215 (TDO and GCS), R01HL130099 (TDO and GCS) and Minnesota Obesity Prevention Training Program T32 NIH Grant T32DK083250 (KAM). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.