Dimethyl Fumarate Attenuates Microglia Activation and Long-Term Memory Deficits Following Systemic Immune Challenge

Hallel C Paraiso, Purdue University

Abstract

Peripheral systemic inflammation is associated with increased cognitive decline and higher risk of developing Alzheimer’s disease. Microglia activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger chronic neurodegeneration. Dimethyl fumarate is a fumaric acid ester approved by the Food and Drug Administration as a treatment for multiple sclerosis. Here, in vitro or in vivo dimethyl fumarate was shown to suppress classical activation of microglia induced by lipopolysaccharide, via reducing co-stimulatory surface molecules and inflammatory mediators. Although the modulation of the inflammatory microglia phenotype through dimethyl fumarate is correlated to activation of the nuclear factor erythroid-2-related factor 2, it was further shown that dimethyl fumarate suppressed the nuclear translocation of nuclear factor kappa beta pathway induced by lipopolysaccharide through a nuclear factor erythroid-2-related factor 2 independent manner. Further investigation showed that dimethyl fumarate alleviated the hyperactive inflammatory microglial response through the downregulation of the inflammatory mediators tumor necrosis factor alpha, interleukin-1 beta, and chemokine ligand 2. Through the modulation of inflammatory microglia, dimethyl fumarate prevented neuronal cell death after exposure to conditioned media generated from lipopolysaccharide-primed microglia. Importantly, dimethyl fumarate treatment rescued long-term memory deficits induced by peripheral lipopolysaccharide challenge. In summary, the results demonstrate a direct effect of DMF on modulation of the microglial phenotype, and dimethyl fumarate treatment protects neurons against toxic microenvironments produced by reactive microglia in response to systemic inflammation.^

Degree

M.S.

Advisors

Elliott J. Blumenthal, Purdue University.

Subject Area

Biology|Neurosciences|Medicine

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