The effect of mGluR2 activation on signal transduction pathways and neuronal cell survival.
In earlier studies, we found profound alterations in specific signal transduction pathways such as mitogen-activated protein kinase signal pathway that mirrored neuronal cell death in Alzheimer disease (AD). To further delineate the mechanism(s) involved in such aberrant signaling, we subsequently showed that mGluR2 is increased in pyramidal neurons in the hippocampus of AD and often co-localizes with neurofibrillary pathology. Based on these data, we suggested that selective neuronal degeneration in AD may arise through the differential expression and activation of specific receptor populations, such as, mGluR2. In this study, to examine the mechanistic relevance of the above-mentioned in vivo findings, we used cell culture models to show that the activation of mGluR2 leads to the activation of extracellular signal-related kinase (ERK) pathways. Importantly, attesting to the in vivo significance of our findings, this pro-survival signaling pathway is also found to be ectopically activated in AD. We also found that the activation of mGluR2 increases the phosphorylation of tau and that the specific activation of mGluR2 reduces oxidative stress mediated cytotoxicity in neuronal cells. Taken together our findings strongly suggest that mGluR2 may participate in mediating the survival of neurons in the face of selective neuronal dysfunction and degeneration in AD. Additionally, our findings lend support to the notion that tau phosphorylation is a neuroprotective antioxidant response to cellular insults.
Lee
Hyoung-gon
HG
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. Hyoung-gon.lee@case.edu
Zhu
Xiongwei
X
Casadesus
Gemma
G
Pallàs
Mercé
M
Camins
Antoni
A
O'Neill
Michael J
MJ
Nakanishi
Shigetada
S
Perry
George
G
Smith
Mark A
MA
D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D016875:tau Proteins; D048049:Extracellular Signal-Regulated MAP Kinases