The inhibition of glycogen synthase kinase 3beta by a metabotropic glutamate receptor 5 mediated pathway confers neuroprotection to Abeta peptides.
Activation of glycogen synthase kinase 3beta (Gsk3beta) has been shown to be a key component in signaling pathways that underlie neurodegeneration and neurodegenerative disease. Conversely, inactivation of Gsk3beta by phosphoinositide 3-kinase (PI3K)/Akt is an important neuroprotective mechanism. Previous studies have shown that agonist activation of group I metabotropic glutamate receptors (mGluRs) can increase neuronal survival and prevent apoptosis. However, little is known about the signaling pathways that couple mGluR5 to neuroprotection. In this report, we investigated whether activation of the PI3K/Akt/Gsk3beta pathway, which has been shown to have an important neuroprotective mechanism, is required for mGluR5 activation mediated neuroprotection against beta-amyloid. We found that brief incubations of mouse hippocampal slices with (R,S)-3,5-dihydroxyphenylglycine (DHPG) resulted in increased phosphorylation of Akt and Gsk3beta. The PI3K inhibitors, LY294002 and wortmannin, blocked the DHPG-induced increased phosphorylation of Akt and Gsk3beta. Similar results were observed in rat primary hippocampal cultures. Finally, we found that the PI3K inhibitor LY294002 can block (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) mediated neuroprotection against beta-amyloid. Thus, these findings suggest that mGluR5 can modulate the PI3K/Akt/Gsk3beta pathway in the hippocampus, and that modulation of this signaling pathway can reverse beta-amyloid-induced neuronal toxicity.
Liu
Feng
F
Wyeth Neuroscience Discovery Research, Princeton, New Jersey 08852, USA. liuf2@wyeth.com
Gong
Xiaohai
X
Zhang
Guoming
G
Marquis
Karen
K
Reinhart
Peter
P
Andree
Terrance H
TH
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D007211:Indoles; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D016229:Amyloid beta-Peptides; D001565:Benzoates; D002867:Chromones; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D007211:Indoles; D008869:Microtubule-Associated Proteins; D009025:Morpholines; C079240:Mtap2 protein, mouse; D010446:Peptide Fragments; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C078592:amyloid beta-protein (1-40); C079694:alpha-methyl-4-carboxyphenylglycine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; C007293:DAPI; D008734:Methoxyhydroxyphenylglycol; C079215:3,5-dihydroxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D005998:Glycine; C010117:3,4-dihydroxyphenylglycol