Scavenger receptor control of chromogranin A-induced microglial stress and neurotoxic cascades.
Chromogranin A (CgA), a neuroactive glycoprotein, is associated with microglial activation cascades implicated in neurodegeneration. Here we show that CgA-dependent inducible nitric oxide synthase (iNOS) expression and stress responses in microglia involved signalling via scavenger receptors (SR), since SR class-A (SR-A) ligands blocked iNOS expression, mitochondrial depolarisation, apoptosis and glutamate release. Furthermore, block of SR-A ameliorated CgA-induced microglial neurotoxicity. In contrast, block of CD36, or the receptor for advanced glycation end products (RAGE) did not prevent CgA-induced microglial activation and neurotoxicity. Thus, manipulation of specific scavenger receptor-coupled signalling pathways may provide avenues for therapeutic intervention in neurodegenerative diseases implicating microglial activation with chromogranin peptides.
Hooper
Claudie
C
Cell Signalling Laboratory, 1 Wakefield Street, Institute of Neurology, University College London, London WC1N 1PJ, UK.
Fry
Victoria A H
VA
Sevastou
Ioanna G
IG
Pocock
Jennifer M
JM
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D053379:Chromogranin A / Q000737:chemistry / Q000633:toxicity*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity*; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051116:Receptors, Scavenger / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D053379:Chromogranin A; D009498:Neurotoxins; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A