Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein (sAPP).
Alzheimer's disease (AD) involves neuronal loss and reduction of synaptic density in specific brain region. Some of the neuronal deaths are associated with excitotoxicity. We previously reported that amyloid beta-peptide (Abeta) induced release of N-methyl-D-aspartate receptor (NMDA-R) co-agonists, including glutamate and D-serine. The induction of D-serine production by Abeta involves transcriptional and/or translational regulation of serine racemase gene. Similarly, we report here that conditioned medium from microglia treated with secreted amyloid precursor protein (sAPP) contained elevated levels of D-serine. In microglia, sAPP increased the steady-state dimeric protein level of serine racemase. Promoter-reporter and mRNA analyses suggested that serine racemase is transcriptionally induced by sAPP. These data extend the link between excitotoxicity and neuroinflammation. D-serine may cooperate with glutamate to link neuroinflammation with excitotoxicity, suggesting a pathogenic mechanism applicable to neuronal death in AD and other neurodegenerative diseases.
Wu
Shengzhou
S
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Basile
Anthony S
AS
Barger
Steven W
SW
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D017628:Microglia / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012694:Serine / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D000099300:Serine Racemase
D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger; D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase