Regulation of amyloid precursor protein secretion by glutamate receptors in human Ntera 2 neurons.
The amyloid precursor protein (APP) can be cleaved by a beta-secretase to generate a beta-amyloid peptide, which has been implicated in the pathogenesis of Alzheimer's disease. However, APP can also be cleaved by an alpha-secretase to form a non-amyloidogenic secreted form of APP (APP-S). APP-S secretion can be physiologically regulated. This study examined the glutamatergic regulation of APP in the human neuronal Ntera 2 (NT2N) cell line. Metabotropic glutamate receptor subtypes 1alpha/beta and 5alpha were identified in the NT2N neurons by reverse transcription-polymerase chain reaction. Stimulation of these phosphatidylinositol-linked receptors with glutamate or specific receptor agonists resulted in a dose- and time-dependent increase in the secretion of the amyloid precursor protein (APP-S), measured by the immunoprecipitation of APP-S from the medium of [35S]methionine-labeled NT2N neurons. The glutamate-induced APP-S secretion was maximal at 30 min and at a concentration of 1 mM glutamate. Glutamate-induced APP-S secretion required activation of phospholipase C, which resulted in inositol 1, 4,5-trisphosphate production, as shown by the rapid glutamate-induced accumulation of inositol 1,4,5-trisphosphate. Glutamate also caused an increase in intracellular Ca2+. The protein kinase C activator phorbol 12-myristate 13-acetate, a phorbol ester, as well as 1-oleoyl-2-acetoyl-3-glycerol, a cell-permeable diacylglycerol analog, also stimulated APP-S secretion. These findings suggest that APP-S secretion from NT2N neurons can be regulated by the activation of phosphatidylinositol-linked metabotropic glutamate receptor signaling pathway.
Jolly-Tornetta
C
C
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Gao
Z Y
ZY
Lee
V M
VM
Wolf
B A
BA
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D017931:DNA Primers; D004075:Diglycerides / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D004075:Diglycerides; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium