title: Reduction of Ether-Type Glycerophospholipids, Plasmalogens, by NF-κB Signal Leading to Microglial Activation.
abstract: Neuroinflammation characterized by activation of glial cells is observed in various neurodegenerative diseases including Alzheimer's disease (AD). Although the reduction of ether-type glycerophospholipids, plasmalogens (Pls), in the brain is reported in AD patients, the mechanism of the reduction and its impact on neuroinflammation remained elusive. In the present study, we found for the first time that various inflammatory stimuli reduced Pls levels in murine glial cells via NF-κB activation, which then downregulated a Pls-synthesizing enzyme, glycerone phosphate O-acyltransferase (Gnpat) through increased c-Myc recruitment onto theGnpatpromoter. We also found that systemic injection of lipopolysaccharide, aging, and chronic restraint stress reduced brain Pls contents that were associated with glial NF-κB activation, an increase in c-Myc expression, and downregulation ofGnpatin the mouse cortex and hippocampus. More interestingly, the reduction of Pls contents in the murine cortex itself could increase the activated phenotype of microglial cells and the expression of proinflammatory cytokines, suggesting further acceleration of neuroinflammation by reduction of brain Pls. A similar mechanism ofGnpatreduction was also found in human cell lines, triple-transgenic AD mouse brain, and postmortem human AD brain tissues. These findings suggest a novel mechanism of neuroinflammation that may explain prolonged progression of AD and help us to explore preventive and therapeutic strategies to treat neurodegenerative diseases.SIGNIFICANCE STATEMENTEther-type glycerophospholipids, plasmalogens (Pls), are reduced in the brain of Alzheimer disease (AD) patients. We found that inflammatory stimuli reduced Pls contents by downregulation of the Pls-synthesizing enzyme glycerone phosphate O-acyltransferase (Gnpat) through NF-κB-mediated recruitment of c-Myc onto theGnpatpromoter in both murine and human cell lines. Murine brains after systemic lipopolysaccharide, chronic stress, and aging, as well as triple-transgenic AD mice and postmortem human AD brain tissues all showed increased c-Myc and reducedGnpatexpression. Interestingly, knockdown ofGnpatitself activated NF-κB in glial cell lines and microglia in mouse cortex. Our findings provide a new insight into the mechanism of neuroinflammation and may help to develop a novel therapeutic approach for neurodegenerative diseases such as AD.
authors.affiliation: Department of Neuroinflammation and Brain Fatigue Science.
authors.forename: Md Shamim
authors.initials: MS
authors.lastname: Hossain
authors.affiliation: Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Department of Integrative Physiology, Graduate School of Medical Sciences, and.
authors.forename: Fatma
authors.initials: F
authors.lastname: Ali
authors.affiliation: Department of Integrative Physiology, Graduate School of Medical Sciences, and.
authors.forename: Mohammed
authors.identifier: 0000-0001-6329-2520
authors.initials: M
authors.lastname: Youssef
authors.affiliation: Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Honsho
authors.affiliation: Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiki
authors.affiliation: Department of Neuroinflammation and Brain Fatigue Science, kataf@physiol.med.kyushu-u.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Katafuchi
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004986:Ether; D020404:Glycerophospholipids / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000494:pharmacology*; D010955:Plasmalogens / Q000378:metabolism*
chemical_list: D020404:Glycerophospholipids; D016328:NF-kappa B; D010955:Plasmalogens; D004986:Ether; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase
keywords: Gnpat; NF-κB; c-Myc; neuroinflammation