Metabotropic glutamate receptor agonists increase release of soluble amyloid precursor protein derivatives from rat brain cortical and hippocampal slices.
The proteolytic processing of the beta-amyloid precursor protein (APP) is regulated by neurotransmitters. Stimulation of metabotropic glutamate receptors (mGluRs) has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs) from cultured cells. We examined the effects of mGluR agonists on APP processing in cortical and hippocampal slices from rat brain. Incubation of the slices in the presence of L-glutamic acid (500 microM), trans-(1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid (1-100 microM) or quisqualic acid (1-100 microM) increased APP release into the medium, relative to the amount of APPs released during incubation in normal Krebs-Ringer buffer under basal conditions. N-Methyl-D-aspartate (1-320 microM), (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (1-100 microM) or kainic acid (5-500 microM) did not alter APP release. The increases in APP release induced by L-glutamic acid (500 microM), trans-(1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid (10 microM) or quisqualic acid (10 microM) were blocked by 100 microM (+/-)-alpha-methyl-4-carboxyphenylglycine, a selective antagonist of mGluRs. Incubation of the slices in the presence of 1 microM phorbol-12-myrisate-13-acetate, an activator of protein kinase C (PKC), also increased APP release, and an inhibitor of PKC, GF-109203X (1 microM), blocked this response as well as the release evoked by mGluR agonists. These data show that activation of mGluR increases APP release from brain slices via PKC-dependent mechanisms.
Ulus
I H
IH
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge 02139-4307, USA.
Wurtman
R J
RJ
D000544:Alzheimer Disease / Q000188:drug therapy; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C