beta-amyloid-induced apoptosis of cerebellar granule cells and cortical neurons: exacerbation by selective inhibition of group I metabotropic glutamate receptors

Administration of beta-amyloid fragment 25-35 (A beta(25-35)) to cultured r at cerebellar granule cells (CGC) or cortical neurons caused cell death tha t was characterized by morphological and nuclear changes consistent with ap optosis. Inhibition of NMDA receptors produced a mild exacerbation of A bet a(25-35) toxicity in cortical neurons; a similar effect was induced by AMPA /kainate receptor inhibition in CGC. Selective activation of group I metabo tropic glutamate receptors (mGluR) by dihyroxyphenylglycine (DHPG) had no e ffect on A beta(25-25)-induced apoptosis in either cell type, and was unaff ected by blockade of ionotropic glutamate receptors. In contrast selective inhibition of group I mGluR by (RS)-1-aminoindan-1,5-dicarboxylic acid (AID A) exacerbated A beta toxicity in cortical neurons, whereas this treatment was without effect on CGC. However, AIDA significantly increased A beta-ind uced apoptosis in CGC in the presence of either NMDA or AMPA/kainate recept or inhibition; blockade of both ionotropic glutamate receptor classes furth er increased the exacerbation of apoptosis following treatment with AIDA. T hese findings suggest that A beta(25-35)-induced neuronal injury leads to a ctivation of group I mGluR, which attenuates the resulting apoptosis. (C) 1 999 Elsevier Science Ltd. All rights reserved.