RRC ID 54067
Author Ali F, Hossain MS, Sejimo S, Akashi K.
Title Plasmalogens Inhibit Endocytosis of Toll-like Receptor 4 to Attenuate the Inflammatory Signal in Microglial Cells.
Journal Mol Neurobiol
Abstract Microglial activation is a pathological feature of many neurodegenerative diseases and the role of cellular lipids in these diseases is mostly unknown. It was known that the special ether lipid plasmalogens (Pls) were reduced in the brain and blood samples of Alzheimer's disease (AD) patients. It has recently been reported that the oral ingestion of scallop-derived Pls (sPls) improved cognition among mild AD patients, which led us to investigate the role of sPls in the microglial activation. We used the lipopolysaccharides (LPS)-induced microglial activation model and found that sPls inhibit the LPS-mediated TLR4 endocytosis and the downstream caspases activation. By using the specific inhibitors, we also confirmed that the TLR4 endocytosis and the caspases activation strictly controlled the pro-inflammatory cytokine expression. In addition, the reduction of cellular Pls by sh-RNA-mediated knockdown of GNPAT (glyceronephosphate O-acyltransferase), a Pls synthesizing enzyme, enhanced the endocytosis of TLR4 and activation of caspase-3 which resulted in the enhanced pro-inflammatory cytokine expression. We also report for the first time that the TLR4 endocytosis was significantly higher in the cortex of aged mice and AD model mice brains, proposing a significant link between the age-related reduction of Pls and microglial activation. Interestingly, the sPls drinking in AD model mice significantly reduced the TLR4 endocytosis. Our cumulative data indicates that the cellular Pls attenuate the microglial activation by maintaining the endocytosis of TLR4, suggesting a possible mechanism of the cognition improvement effect of sPls among mild AD patients.
Volume 56(5)
Pages 3404-3419
Published 2019-5-1
DOI 10.1007/s12035-018-1307-2
PII 10.1007/s12035-018-1307-2
PMID 30128650
MeSH Acyltransferases / metabolism Aging / pathology Alzheimer Disease / pathology Animals Brain / pathology Caspase 3 / metabolism Caspase 8 / metabolism Cell Nucleus / metabolism Cytokines / metabolism Dynamins / metabolism Endocytosis / drug effects* Enzyme Activation HEK293 Cells Humans Inflammation / metabolism* Inflammation / pathology* Interleukin-1beta / metabolism Lipopolysaccharides / pharmacology Membrane Microdomains / metabolism Mice, Inbred C57BL Microglia / drug effects Microglia / metabolism* Microglia / pathology NF-kappa B / metabolism Plasmalogens / pharmacology* RNA, Small Interfering / metabolism Signal Transduction* Toll-Like Receptor 4 / metabolism*
IF 4.5
Times Cited 2
Human and Animal Cells 293(RCB1637)