The role of FUT8‐catalyzed core fucosylation in Alzheimer's amyloid‐β oligomer‐induced activation of human microglia

Lee‐Way Jin; Jacopo Di Lucente; Ulises Ruiz Mendiola; Xinyu Tang; Angela M. Zivkovic; Carlito B. Lebrilla; Izumi Maezawa

doi:10.1002/glia.24345

journal article Jan 24, 2023

The role of FUT8‐catalyzed core fucosylation in Alzheimer's amyloid‐β oligomer‐induced activation of human microglia

Lee‐Way Jin Jacopo Di Lucente

Ulises Ruiz Mendiola Xinyu Tang

Angela M. Zivkovic

Carlito B. Lebrilla

Izumi Maezawa

Glia Vol. 71 No. 5 pp. 1346-1359 · Wiley

View at Publisher Save 10.1002/glia.24345

Abstract

AbstractFucosylation, especially core fucosylation of N‐glycans catalyzed by α1‐6 fucosyltransferase (fucosyltransferase 8 or FUT8), plays an important role in regulating the peripheral immune system and inflammation. However, its role in microglial activation is poorly understood. Here we used human induced pluripotent stem cells‐derived microglia (hiMG) as a model to study the role of FUT8‐catalyzed core fucosylation in amyloid‐β oligomer (AβO)‐induced microglial activation, in view of its significant relevance to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO and lipopolysaccharides (LPS) with a pattern of pro‐inflammatory activation as well as enhanced core fucosylation and FUT8 expression within 24 h. Furthermore, we found increased FUT8 expression in both human AD brains and microglia isolated from 5xFAD mice, a model of AD‐like cerebral amyloidosis. Inhibition of fucosylation in AβO‐stimulated hiMG reduced the induction of pro‐inflammatory cytokines, suppressed the activation of p38MAPK, and rectified phagocytic deficits. Specific inhibition of FUT8 by siRNA‐mediated knockdown also reduced AβO‐induced pro‐inflammatory cytokines. We further showed that p53 binds to the two consensus binding sites in the Fut8 promoter, and that p53 knockdown abolished FUT8 overexpression in AβO‐activated hiMG. Taken together, our evidence supports that FUT8‐catalyzed core fucosylation is a signaling pathway required for AβO‐induced microglia activation and that FUT8 is a component of the p53 signaling cascade regulating microglial behavior. Because microglia are a key driver of AD pathogenesis, our results suggest that microglial FUT8 could be an anti‐inflammatory therapeutic target for AD.

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Citations

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References

Details

Published: Jan 24, 2023
Vol/Issue: 71(5)
Pages: 1346-1359
License: View

Authors

L

Lee‐Way Jin

Department of Pathology and Laboratory Medicine and M.I.N.D. Institute University of California Davis Medical Center Sacramento California USA

J

Jacopo Di Lucente

Department of Pathology and Laboratory Medicine and M.I.N.D. Institute University of California Davis Medical Center Sacramento California USA

U

Ulises Ruiz Mendiola

Department of Pathology and Laboratory Medicine and M.I.N.D. Institute University of California Davis Medical Center Sacramento California USA

X

Xinyu Tang

Department of Nutrition University of California Davis California USA

A

Angela M. Zivkovic

Department of Nutrition University of California Davis California USA

C

Carlito B. Lebrilla

Department of Chemistry University of California Davis California USA

I

Izumi Maezawa

Department of Pathology and Laboratory Medicine and M.I.N.D. Institute University of California Davis Medical Center Sacramento California USA

Funding

National Institute on Aging Award: P30 AG072972

Cite This Article

Lee‐Way Jin, Jacopo Di Lucente, Ulises Ruiz Mendiola, et al. (2023). The role of FUT8‐catalyzed core fucosylation in Alzheimer's amyloid‐β oligomer‐induced activation of human microglia. Glia, 71(5), 1346-1359. https://doi.org/10.1002/glia.24345

The role of FUT8‐catalyzed core fucosylation in Alzheimer's amyloid‐β oligomer‐induced activation of human microglia

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