Abstract

The proteolytic processing of the β-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 μM),trans-(1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid (1–100 μM) or quisqualic acid (1–100 μM) 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 μM), (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (1–100 μM) or kainic acid (5–500 μM) did not alter APP release. The increases in APP release induced by l-glutamic acid (500 μM),trans-(1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid (10 μM) or quisqualic acid (10 μM) were blocked by 100 μM (±)-α-methyl-4-carboxyphenylglycine, a selective antagonist of mGluRs. Incubation of the slices in the presence of 1 μM phorbol-12-myrisate-13-acetate, an activator of protein kinase C (PKC), also increased APP release, and an inhibitor of PKC, GF-109203X (1 μM), 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.