Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors.
Stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol and activating protein kinase C, accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, nonamyloidogenic derivatives (APPs), as previously shown. This relationship has been demonstrated in human glioma and neuroblastoma cells, as well as in transfected human embryonic kidney 293 cells and PC-12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to phosphatidylinositol 4,5-bisphosphate hydrolysis, similarly accelerates processing of APP into nonamyloidogenic APPs. This process is demonstrated both in hippocampal neurons derived from fetal rats and in human embryonic kidney 293 cells transfected with cDNA expression constructs encoding the mGluR 1 alpha subtype. In hippocampal neurons, both an mGluR antagonist, L-(+)-2-amino-3-phosphonopropionic acid, and an inhibitor of protein kinase C, GF 109203X, blocked the APPs release evoked by glutamate receptor stimulation. Ionotropic glutamate agonists, N-methyl-D-aspartate or S(-)-5-fluorowillardiine, failed to affect APPs release. These data show that selective mGluR agonists that initiate signal-transduction events can regulate APP processing in bona fide primary neurons and transfected cells. As glutamatergic neurons in the cortex and hippocampus are damaged in Alzheimer disease, amyloid production in these regions may be enhanced by deficits in glutamatergic neurotransmission.
Lee
R K
RK
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139, USA.
Wurtman
R J
RJ
Cox
A J
AJ
Nitsch
R M
RM
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D005333:Fetus; D005910:Glioma; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007668:Kidney; D007700:Kinetics; D008301:Maleimides / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational; D011743:Pyrimidines / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D007211:Indoles; D008301:Maleimides; D009498:Neurotoxins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011743:Pyrimidines; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C000211:2-amino-3-phosphonopropionic acid; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C095178:5-fluorowillardiine; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D011493:Protein Kinase C; D011796:Quinacrine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; D000409:Alanine