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 (Abeta25-35) to cultured rat cerebellar granule cells (CGC) or cortical neurons caused cell death that was characterized by morphological and nuclear changes consistent with apoptosis. Inhibition of NMDA receptors produced a mild exacerbation of Abeta25-35 toxicity in cortical neurons; a similar effect was induced by AMPA/kainate receptor inhibition in CGC. Selective activation of group I metabotropic glutamate receptors (mGluR) by dihyroxyphenylglycine (DHPG) had no effect on Abeta25-35-induced apoptosis in either cell type, and was unaffected by blockade of ionotropic glutamate receptors. In contrast, selective inhibition of group I mGluR by (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) exacerbated Abeta toxicity in cortical neurons, whereas this treatment was without effect on CGC. However, AIDA significantly increased Abeta-induced apoptosis in CGC in the presence of either NMDA or AMPA/kainate receptor inhibition; blockade of both ionotropic glutamate receptor classes further increased the exacerbation of apoptosis following treatment with AIDA. These findings suggest that Abeta25-35-induced neuronal injury leads to activation of group I mGluR, which attenuates the resulting apoptosis.
Allen
J W
JW
Institute for Cognitive and Computational Sciences, Georgetown University Medical Center, Washington, DC 20007, USA.
Eldadah
B A
BA
Faden
A I
AI
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D011810:Quinoxalines; D018094:Receptors, Metabotropic Glutamate; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C104077:metabotropic glutamate receptor type 1; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016291:Dizocilpine Maleate